rs6962

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004168.4(SDHA):c.1969G>A(p.Val657Ile) variant causes a missense change. The variant allele was found at a frequency of 0.128 in 1,605,264 control chromosomes in the GnomAD database, including 11,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V657L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2763 hom., cov: 34)

Exomes 𝑓: 0.12 ( 8375 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011221588).

BP6

Variant 5-256394-G-A is Benign according to our data. Variant chr5-256394-G-A is described in ClinVar as [Benign]. Clinvar id is 130279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-256394-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1969G>A	p.Val657Ile	missense_variant	15/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1969G>A	p.Val657Ile	missense_variant	15/15	1	NM_004168.4	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26620

AN:

151644

Hom.:

2756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.0559

Gnomad SAS

AF:

0.0850

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.131

AC:

32957

AN:

250898

Hom.:

2221

AF XY:

0.126

AC XY:

17130

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.169

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.0602

Gnomad SAS exome

AF:

0.0879

Gnomad FIN exome

AF:

0.0855

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.123

AC:

178656

AN:

1453502

Hom.:

8375

Cov.:

AF XY:

0.121

AC XY:

87874

AN XY:

723584

show subpopulations

Gnomad4 AFR exome

AF:

0.308

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.0476

Gnomad4 SAS exome

AF:

0.0871

Gnomad4 FIN exome

AF:

0.0873

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.176

AC:

26650

AN:

151762

Hom.:

2763

Cov.:

AF XY:

0.170

AC XY:

12640

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.316

Gnomad4 AMR

AF:

0.178

Gnomad4 ASJ

AF:

0.156

Gnomad4 EAS

AF:

0.0554

Gnomad4 SAS

AF:

0.0855

Gnomad4 FIN

AF:

0.0812

Gnomad4 NFE

AF:

0.120

Gnomad4 OTH

AF:

0.174

Alfa

AF:

0.112

Hom.:

433

Bravo

AF:

0.196

TwinsUK

AF:

0.128

AC:

474

ALSPAC

AF:

0.129

AC:

496

ESP6500AA

AF:

0.326

AC:

1438

ESP6500EA

AF:

0.130

AC:

1117

ExAC

AF:

0.131

AC:

15857

Asia WGS

AF:

0.0970

AC:

341

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.128

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex II deficiency, nuclear type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Leigh syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Paragangliomas 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

SDHA-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Benign

0.72

DEOGEN2

Benign

0.24

T;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.000017

P;P;P

PrimateAI

Uncertain

0.54

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.021, 0.013

.;B;B;.

Vest4

0.15

MPC

0.41

ClinPred

0.017

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.031

gMVP

0.50

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