chr3-37048973-C-T

Position:

chr3-37048973-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_000249.4(MLH1):c.2059C>T(p.Arg687Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,936 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R687G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:22U:1

Conservation

PhyloP100: 4.98

Variant links:

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 links:

MLH1 (HGNC:):

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37048973-C-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 3-37048973-C-T is Pathogenic according to our data. Variant chr3-37048973-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90014.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048973-C-T is described in Lovd as [Pathogenic]. Variant chr3-37048973-C-T is described in Lovd as [Benign]. Variant chr3-37048973-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.2059C>T	p.Arg687Trp	missense_variant	18/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.2059C>T	p.Arg687Trp	missense_variant	18/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000199

AC:

AN:

251196

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727214

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2024	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: 18383312, 22949379, 23760103, 16042583, 24362816, 16395668, 15845562, 27629256, 18709565, 31830689, 29922827, 17510385, 21120944, 22736432, 22949387, 25525159, 11139242, 17192056, 15289847, 24440087, 22180144, 14762794, 11748856, 11920458, 11920650, 12362047, 16451135, 17312306, 18566915, 22120844, 21404117, 19267393, 27300758, 27152634, 27831900, 28874130, 29288294, 27601186, 25430799, 22290698, 16288214, 30521064, 30720243, 30787465, 33087929, 26485756, 34873480, 12799449, 20533529, 22753075, 19697156, 31391288, 35430768) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 13, 2024	The MLH1 c.2059C>T (p.Arg687Trp) variant has been reported in the published literature in multiple individuals and families with Lynch syndrome, including as a founder mutation in the Swedish population (PMID: 29288294 (2018), 28874130 (2017), 27152634 (2016), 26485756 (2015), 21404117 (2011), 19697156 (2009), 17312306 (2007), 11920650 (2002), 11920458 (2002), 12362047 (2002), 11139242 (2001)). It has also been reported as homozygous in three siblings with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 14762794 (2004)). Functional evidence for this variant is inconclusive since one experimental study showed that this variant reduced in-vitro MMR activity and MLH1 expression (PMID: 17510385(2007)) and another study showed that this variant was comparable to the wildtype MLH1 in its expression and MMR efficiency (PMID: 19697156 (2009)). The variant was shown to segregate with disease in multiple families (PMID: 19267393 (2009), 19697156 (2009), 14762794 (2004), 11920650 (2002)). The frequency of this variant in the general population, 0.000098 (3/30612 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 12, 2014	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.2059C>T (p.Arg687Trp) missense variant has been reported in in individuals and families affected with Lynch syndrome, constitutional mismatch repair deficiency syndrome, as well as colorectal and gastrointestinal cancer (Jakubowska et al., 2001; Godino et al., 2001). In several families, this variant cosegregated with disease (Godino et al., 2001). An experimental study has shown that this variant affects mismatch repair activity in yeast-based functional assays, and MLH1 protein expression in vitro (Takahashi et al., 2007). This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arg at position 687 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg687Trp in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jun 18, 2022	ACMG criteria used to clasify this variant: PM1, PM2, PP3, PP2, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 15, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11920650, 14762794]. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 26, 2023	The MLH1 c.2059C>T (p.Arg687Trp) missense change has a maximum subpopulation frequency of 0.0098% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, and a functional study in yeast demonstrated a reduction in MMR activity and MLH1 protein expression (PMID: 17510385). This variant has been reported as heterozygous in individuals with a personal and/or family history of Lynch syndrome (PMID: 11139242, 11748856, 11920458, 11920650, 12362047, 17312306, 18566915, 19697156, 27152634, 29288294). It has also been reported as homozygous in multiple unrelated individuals with constitutional mismatch repair deficiency (PMID: 14762794, 24440087). In summary, this variant meets criteria to be classified as pathogenic. -

Lynch syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2019	Variant summary: MLH1 c.2059C>T (p.Arg687Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (IPR032189) 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 2e-05 in 251916 control chromosomes (gnomAD). It has also has been reported in the literature in multiple individuals and families affected with Lynch syndrome, constitutional mismatch repair deficiency syndrome, colorectal and gastrointestinal cancers from different populations (e.g. Arnold_2009, Caldes_2002; Lagerstedt Robinson_2007; Furukawa_2002, Bakry_2014, Gallinger_2004). The variant co-segregated with the disease in multiple families (e.g. Arnold_2009, Caldes_2002, Christensen_2009) but not in all (Lagerstedt Robinson_2007). In addition, International Society for Gastrointestianl Heriditary Tumors (InSiGHT) and others have performed systematic investigation and classified this variant as pathogenic (Tricarico_2017). These data indicate that the variant is very likely to be associated with disease. One experimental study demonstrated that this variant affects function in yeast functional assays and reduce in vitro MMR activity and MLH1 expression (Takahashi_2007). In contrast Christensen et al (Christensen_2009) has shown that this variant behaved like WT-MLH1 in its expression, MMR efficiency and subcellular localization. Six submitters have provided clinical significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They classified the variant as pathogenic (4x) /likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability >0.99 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Arg687Trp variant in MLH1 has been previously reported in at least 16 individuals with Lynch syndrome (von Salome 2018, Jakubowska 2001, Furukawa 2002, Caldes 2002) and 3 homozygous siblings affected with constitutive mismatch repair deficiency (Durno 2012). It is considered a founder mutation for Lynch syndrome in Sweden (von Salome 2018). It has also been identified in 3/30612 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic by several clinical labs in ClinVar and on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 90014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant mildly impacts protein function (Takahashi 2007, Christensen 2009, Kansikas 2011); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PS4, PP1_Strong, PM3, PM2_Supporting, PP4. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 21, 2024	The p.R687W pathogenic mutation (also known as c.2059C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2059. The arginine at codon 687 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in the heterozygous state in multiple families with Lynch syndrome (Jakubowska A et al. Hum Mutat, 2001;17:52-60; Godino J et al. Hum. Mutat., 2001 Dec;18:549;Furukawa T et al. Cancer, 2002 Feb;94:911-20; Caldes T et al. Int J Cancer, 2002 Apr;98:774-9; Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Zumstein V et al. Swiss Med Wkly, 2016 May;146:w14315; von Salomé J et al. Fam Cancer, 2017 Dec). One study reported segregation with disease in a large kindred (LOD score 1.5), including multiple individuals diagnosed with colon and/or endometrial cancer (Christensen LL et al. Fam Cancer, 2009 Aug;8:489-500). This mutation has also been observed in the homozygous state in multiple individuals from unrelated families with constitutional mismatch repair deficiency (CMMRD) syndrome (Gallinger S et al. Gastroenterology, 2004 Feb;126:576-85; Bakry D et al. Eur. J. Cancer, 2014 Mar;50:987-96). In one functional study, this mutation demonstrated lack of a dominant mutator effect (DME) and reduced MLH1 protein expression in yeast assays (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). 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 variant is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 17, 2021	This missense variant replaces arginine with tryptophan at codon 687 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in functional DNA repair in vitro and normal protein stability (PMID: 17510385, 19697156). This variant has been reported in individuals affected with Lynch syndrome (PMID: 11748856, 11920458, 18566915, 19267393, 19697156, 21404117, 25430799, 27629256, 28874130, 29288294), CMMRD (24440087), colorectal cancer (PMID: 26485756, 27152634), or ovarian cancer (PMID: 19697156). This variant has been identified in 5/251196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Carcinoma of colon

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MLH1 p.Arg687Trp variant was identified in 15 of 7816 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and constitutional biallelic mismatch repair deficiency syndrome, and was not identified in 3420 control chromosomes from healthy individuals (Lagerstedt-Robinson 2016, von Salome 2017, Zumstein 2016, Bakry 2014, Caldes 2002, Gallinger 2004). The variant was also identified in the following databases: dbSNP (ID: rs63751275) as "With Pathogenic, Uncertain significance allele", ClinVar (4x likely pathogenic, 3x pathogenic including review by expert panel InSiGHT), Clinvitae, Cosmic (1x, confirmed somatic, in carcinoma of the large intestine), UMD-LSDB (6x, unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (58x, pathogenic). The variant was not identified in GeneInsight-COGR, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 245948 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15302 chromosomes (freq: 0.00007), European in 1 of 111454 chromosomes (freq: 0.000009), and South Asian in 3 of 30778 chromosomes (freq: 0.0001). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. Functional studies show conflicting results; a study by Christensen 2009 found protein expression, repair efficiency, and subcellular localization of the variant protein similar to wildtype MLH1. However, a study by Takahashi 2007 demonstrated a pathogenic phenotype in three functional assays in yeast, as well as reduced protein expression and mismatch repair activity. No effect in splicing was found in a cDNA splicing assay (Borras 2012). This variant has been found in a homozygous state in children diagnosed with constitutional biallelic mismatch repair deficiency syndrome (Gallinger 2004, Bakry 2014). In several families, this variant co-segregated with disease (Caldes 2002, Christensen 2009, Zumstein 2016). Although the p.Arg687 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg687Trp variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

MLH1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The MLH1 c.2059C>T variant is predicted to result in the amino acid substitution p.Arg687Trp. This variant is considered to be a founder variant in the Swedish population and has been reported in individuals with hereditary non-polyposis colorectal cancer (Jakubowska et al. 2001. PubMed ID: 11139242), mismatch repair deficiency syndromes (Bakry et al. 2014. PubMed ID: 24440087), and Lynch syndrome (von Salomé et al. 2018. PubMed ID: 29288294). Functional studies have been discrepant regarding the impact of this variant on MLH1 function with reports ranging from wild type activity (Christensen et al. 2009. PubMed ID: 19697156) to reduced expression and MMR activity (Takahashi et al. 2007. PubMed ID: 17510385). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic by an expert review panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90014). This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 687 of the MLH1 protein (p.Arg687Trp). This variant is present in population databases (rs63751275, gnomAD 0.01%). This missense change has been observed in individuals with Lynch syndrome, constitutional mismatch repair deficiency syndrome, as well as colorectal and gastrointestinal cancer (PMID: 11139242, 11748856, 11920650, 14762794, 19697156, 21404117, 24440087, 26485756). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90014). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379, 22949387, 24362816). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 16395668, 17510385). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Ding PR Lab, Sun Yat-sen University Cancer Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

D;D;.;.;.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.78

MutPred

0.82

Loss of disorder (P = 0.024);.;.;.;.;.;

MVP

0.97

MPC

0.40

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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