11-112088939-C-T

Position:

chr11-112088939-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_003002.4(SDHD):c.242C>T(p.Pro81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,648 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P81P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24O:2

Conservation

PhyloP100: 5.74

Variant links:

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

SDHD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a transmembrane_region Helical (size 21) in uniprot entity DHSD_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003002.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 11-112088939-C-T is Pathogenic according to our data. Variant chr11-112088939-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088939-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	3/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	3/4	1	NM_003002.4	ENSP00000364699	P1	O14521-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251420

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461466

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 1

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 27, 2023	This missense variant replaces proline with leucine at codon 81 of the SDHD 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 succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 09, 2022	The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the SDHD gene, which is predicted to change the amino acid proline at position 81 in the protein to leucine. The variant has been reported in many patients with paraganglioma and has been suggested to be a founder variant (PMID:10657297, 11391796, 11897812, 19454582,21348866, 23433498, 25494863) (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2). This variant co-segregates with disease (PMID:21937622, 10657297, 29386252) (PP1_strong). Computational predictions strongly support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs80338844) and as disease causing in the HGMD database (CM000207). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6896). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 09, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24758185, 28179334, 30050099]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29386252, 30877234, 30050099, 32098148]. -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jan 21, 2014	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2021	The SDHD c.242C>T; p.Pro81Leu variant (rs80338844) is one of the most common variants reported in familial and sporadic cases of head and neck paraganglioma (PGL) (Andrews 2018, Astrom 2003, Baysal 2000, Baysal 2002, Sridhara 2013, Xekouki 2015). It has been reported to co-segregate with disease in several affected families (Astrom 2003, Baysal 2000, Xekouki 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6896), and it is observed on only six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 81 is well conserved across a variety of species and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Astrom K et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet. 2003 Aug;113(3):228-37. Baysal BE et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000 Feb 4;287(5454):848-51. Baysal BE et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002 Mar;39(3):178-83. Sridhara SK et al. Genetic testing in head and neck paraganglioma: who, what, and why? J Neurol Surg B Skull Base. 2013 Aug;74(4):236-40. Xekouki P et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 06, 2022	The frequency of this variant in the general population, 0.000021 (6/282810 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with paraganglioma and/or pheochromocytoma (PMIDs: 30877234 (2019), 30375904 (2018), 29625052 (2018), 25494863 (2015), 24436918 (2013), 23433498 (2013), 21348866 (2012), 21348866 (2011), 19454582 (2009), 15479192 (2004), 11897817 (2002), 11391796 (2001), 10657297 (2000)), and is found to co-segregate with disease in multiple families (PMIDs: 11391796 (2001) and 21937622 (2011)). An experimental study using a humanized yeast construct has reported this variant results in oxidative growth, SDH activity, oxygen consumption and mtDNA mutability similar to WT (PMID: 23175444 (2013), however, studies using tumor tissue have demonstrated that this variant results in reduced enzyme activity (PMID: 24758185) and increased fumarate:succinate ratio (PMID: 24758185 (2014) and 30050099 (2019)). 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, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2023	PP1_strong, PP3, PP4, PM2, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 23175444, 15328326, 28748451, 25494863, 19454582, 24758185, 30375904, 29386252, 11156372, 26259135, 25014000, 11897817, 11343322, 11391798, 12811540, 19802898, 26916530, 11391796, 26113606, 25326637, 25695889, 22290790, 15235042, 14974914, 17102085, 15479192, 10657297, 28179334, 29341163, 24102379, 23433498, 21348866, 24436918, 29681642, 30658386, 29777207, 30050099, 30877234, 22575350, 29625052, 31492822, 32741965, 30787465, 33087929) -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:3Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 06, 2023	This missense variant replaces proline with leucine at codon 81 of the SDHD 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 succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2016	The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 200 2, Mannelli 2006, Astrom 2003). This variant, along with loss of heterozygosity, has also been found as a somatic change in the tumor of an individual with an i solated pheochromocytoma (Gimm 2000). It has also been reported by other clinica l laboratories in ClinVar (Variation ID 6896). This variant has also been identi fied in 3/126674 of European chromosomes by the Genome Aggregation Database (gno mAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low e nough to be consistent with the frequency of hereditary PGL/PCC syndrome in the general population. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndrome in an autosoma l dominant manner based upon segregation studies and presence in multiple affect ed individuals. ACMG/AMP Criteria applied: PS4, PP1_Strong (Richards 2015). -

Pheochromocytoma

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 12, 2022	The c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is a known Pathogenic variant that has been reported in multiple familial and sporadic cases of head and neck paraganglioma or pheochromocytoma [PMID: 10657297, 29625052, 15479192, 30375904, 11391796, 11897817,30877234], and has been deposited in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 6896]. In one study, of 53 individuals with detailed clinical information and carrying the p.(Pro81Leu) variant, 15 were asymptomatic, 37 had head and neck paraganglioma (HNPGL) (two metastatic) and 1 had phaeochromocytoma and paraganglioma (PPGL). Authors concluded that the p.(Pro81Leu) variant carriers manifest almost exclusively with HNPGL, while other SDHD pathogenic variants predispose to both HNPGL and PPGL [PMID: 29386252]. The c.242C>T variant is observed in 8 out of 590,232 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The variant is located in exon 3 of this 4-exon gene, and is predicted to replace an evolutionarily conserved Proline amino acid with Leucine at position 81 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Pro81Leu) [REVEL score = 0.91]. Based on available evidence, the c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is reported as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121894 control chromosomes tested in ExAC and published control cohorts. The variant has been reported in numerous patients, and has been found segregating with disease in families as well as in sporadic, non-familial cases. Based on the literature, the variant is considered a founder mutation and a well-known pathogenic allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 15, 2021	The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This alteration has been described in numerous cases of familial paraganglioma/pheochromocytoma (PGL-PCC), multifocal PGL-PCC, and sporadic PGL-PCC (Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37; Milunsky JM et al. Am. J. Med. Genet. 2001 May;100(4):311-4; Shulskaya MV et al. Int J Neurosci, 2018 Dec;128:1174-1179; Enríquez-Vega ME et al. Cir Cir, 2019;86:33-37; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Richter S et al. Genet Med, 2019 03;21:705-717; (Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Smith JD et al. OTO Open Mar;5:2473974X21995453) and has been shown to segregate with disease in PGL kindreds (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Yeap PM et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2009-13). A study consisting of 170 individuals with SDHD mutations, p.P81L carriers had a significantly lower risk for pheochromocytoma compared to other SDHD mutations (p=0.031) and presented almost exclusively with head/neck PGLs (Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). One study reported that this alteration results in an increased succinate:fumarate ratio and decreased SDHD enzymatic activity; although the alteration produced a false-negative result using succinate:fumarate ratio in a different study using enzymatic levels as a method for screening for SDH mutations in a tumor with loss of heterozygosity and reduced SDH activity (Canu L et al. J. Clin. Endorcinol. Metab. 2014 Jul;99(7):2321-6; Richter S et al. J. Clin. Endocrinol. Metab. 2014 Oct;99(10):3903-11). It is believed that both founder effects and mutation recurrence contribute to the prevalence of this alteration in North America (Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jan 25, 2022

PS4, PM2, PP3 -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the SDHD protein (p.Pro81Leu). This variant is present in population databases (rs80338844, gnomAD 0.006%). This missense change has been observed in individual(s) with head and neck paraganglioma (HNP) or pheochromocytoma (PMID: 10657297, 11391796, 11897817, 15479192, 19454582, 21348866, 21937622, 23433498, 24436918, 25494863). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex 2 deficiency, nuclear type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 09, 2024

- -

SDHD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The SDHD c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has previously been reported in multiple individuals and families with paraganglioma and pheochromocytoma (Baysal et al. 2000. PubMed ID: 10657297; Hensen et al. 2012. PubMed ID: 21348866; Sridhara et al. 2013. PubMed ID: 24436918; Dénes et al. 2015. PubMed ID: 25494863). This variant is also known as c.125C>T (p.Pro42Leu) using an alternative transcript (NM_001276504.1). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. In ClinVar, the SDHD variant is reported as pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6896/). This variant is interpreted as pathogenic. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Paragangliomas 1;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D;.;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;M;.;.;M;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-9.3

D;.;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Benign

0.033

D;.;D;D;D;D

Sift4G

Benign

0.29

T;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.89

MutPred

0.94

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;

MVP

0.97

MPC

0.61

ClinPred

0.84

GERP RS

5.0

Varity_R

0.81

gMVP

0.88

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

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