chr17-7675139-C-T

Position:

chr17-7675139-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The ENST00000269305.9(TP53):c.473G>A(p.Arg158His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000269305.9

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675138-GC-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 568285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 17-7675139-C-T is Pathogenic according to our data. Variant chr17-7675139-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675139-C-T is described in Lovd as [Pathogenic]. Variant chr17-7675139-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.473G>A	p.Arg158His	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.473G>A	p.Arg158His	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251268

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); Observed in a few individuals not meeting classic Li-Fraumeni syndrome criteria but several with adrenocortical carcinoma (ACC), leading some authors to suggest this variant might cause reduced penetrance or later onset of tumors other than ACC similar to the TP53 Arg337His Brazilian founder variant (PMID: 26014290, 20455025, 21464421); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20308654, 14559903, 9738975, 21665242, 24590827, 22768918, 27343442, 24764719, 12826609, 26786923, 16494995, 17311302, 21761402, 23894400, 27619989, 18511570, 25584008, 11896595, 9115587, 9399658, 10519380, 12917626, 20522432, 20455025, 21343334, 21464421, 20593220, 21552135, 21601526, 23117049, 25773284, 24829203, 24868540, 24198462, 19671995, 26014290, 23175693, 10486318, 10229196, 28369373, 27501770, 27157322, 28408749, 18685109, 29085664, 28749946, 28466600, 28922847, 28597078, 29058986, 27844328, 25234657, 22170717, 21339461, 10864200, 28349240, 27328919, 25741868, 29755662, 29707145, 28887601, 28724667, 17606709, 11429705, 17308077, 29300620, 29979965, 31016814, 30840781, 31081129, 30092803, 30224644, 31494577, 31447099, 30720243, 31105275, 32427313, 32817165, 33372952, 34240179, 31721094, 33858029, 34308104, 34863587, 35974385, 35418818, 34273903, 35988656, 36495689, 37461096, 12909720, 28472496, 15510160, 37179382) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 21, 2022	The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (LFS), breast cancer, acute myeloid leukemia, and Li Fraumeni Syndrome associated cancers (PMIDs: 33372952 (2020), 32427313 (2020), 31105275 (2019), 31081129 (2019), 27501770 (2016), 26014290 (2015), 23894400 (2013), 22186996 (2012), 21761402 (2012), 21601526 (2011), 21464421 (2011)). Published functional studies have reported that this variant results in a damaging affect on TP53 protein function (PMIDs: 28472496 (2017), 25584008 (2015), 20522432 (2010), IARC TP53 https://p53.iarc.fr/). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Li-Fraumeni syndrome 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is not observed at significant frequency in large population cohorts (gnomAD) . This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141963). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Also,advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, aminoacid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TP53 protein function. (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Dec 10, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196]. -

Li-Fraumeni syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 13, 2018	The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2022	Variant summary: TP53 c.473G>A (p.Arg158His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes.c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits a significantly decreased transactivation activity (PMID: 10229196, 12826609, 21343334, 25584008, 28472496) and cell growth control activity (PMID: 10229196, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 18685109, 20522432, 21552135, 31081129, 34540492) and in individuals fulfilling the Chompret criteria for Li-Fraumeni syndrome (PMID: 10486318, 10864200, 17308077, 20455025, 21601526, 23175693, 23894400, 24764719, 25584008, 26014290, 27501770, 28472496, 30092803; Lu et al 2021, DOI: 10.1158/1538-7445.AM2021-810). Ages of onset ranged from childhood to adulthood, and several carriers were reported to be unaffected (PMID: 17308077, 21601526, 27501770, 28472496). This variant has been shown to segregate with disease in multiple families (PMID: 17308077, 21464421, 24764719, 34540492; IARC database), including a family with a proband affected with malignant peritoneal mesothelioma and her five first-degree relatives affected with Li-Fraumeni syndrome spectrum tumors (PMID: 21464421). This variant has been identified in 1/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense substitutions occurring at the same codon (p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been observed in individuals affected with Li-Fraumeni syndrome and have been shown to disrupt TP53 function (ClinVar variation ID: 856171, 528248, 246118). This indicates arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2022	The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 473. The arginine at codon 158 is replaced by histidine, an amino acid with some highly similar properties. This alteration has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome, with ages of onset ranging from childhood to adulthood (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). In a study of 214 French families with Li-Fraumeni syndrome, this alteration was identified in eight families; six of these families had cases of adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, a recent functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). Furthermore, three different TP53 missense mutations at the same codon have been reported to be associated with Li-Fraumeni syndrome: p.R158G, p.R158P, and p.R158C (Chompret A et al. Br J Cancer. 2000; 82(12):1932-7; Morgan JE et al. Hum Mutat. 2010;31(4):484-91; Herrmann LJ et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E476-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	May 18, 2023	c.473G>A, located in exon 5 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 158, p.(Arg158His). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C25; BayesDel: 0.53) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 10486318, 17308077, 20522432, 23175693, 24764719) (PS4). The variant co-segregates in affected individuals (3 meiosis, 2 families) (PMID: 17308077, 24764719). It has been reported in ClinVar (15x as pathogenic, 4x as likely pathogenic) and CancerHotspots (36 somatic observations, PM1). Based on the currently available information, c.473G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 24, 2023

- -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 23, 2022

- -

Rhabdomyosarcoma

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Choroid plexus papilloma;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS3_Moderate+PM5+PS4+PP1_Moderate -

TP53-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.83

D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D

Eigen

Benign

0.19

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.1

.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.8

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0

D;.;.;.;.;.;P;.;P;D;P;.;.;P;.;.;.;D;.

Vest4

0.97

MutPred

0.99

Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);.;.;.;.;Loss of methylation at R158 (P = 0.0308);.;Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);.;.;Loss of methylation at R158 (P = 0.0308);.;.;.;.;Loss of methylation at R158 (P = 0.0308);

MVP

1.0

MPC

1.2

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over