5-223531-A-T

Position:

chr5-223531-A-T

Variant summary

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

The NM_004168.4(SDHA):c.113A>T(p.Asp38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,613,484 control chromosomes in the GnomAD database, including 1,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D38N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 84 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1676 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.74

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=0.002396673).

BP6

Variant 5-223531-A-T is Benign according to our data. Variant chr5-223531-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 224957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-223531-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0518 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.113A>T	p.Asp38Val	missense_variant	2/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	2/15	1	NM_004168.4	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4494

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00827

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0507

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0569

Gnomad FIN

AF:

0.0255

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0448

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0351

AC:

8822

AN:

251180

Hom.:

223

AF XY:

0.0381

AC XY:

5167

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0503

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0590

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0456

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0438

AC:

64049

AN:

1461154

Hom.:

1676

Cov.:

AF XY:

0.0446

AC XY:

32425

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00547

Gnomad4 AMR exome

AF:

0.0144

Gnomad4 ASJ exome

AF:

0.0503

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0604

Gnomad4 FIN exome

AF:

0.0243

Gnomad4 NFE exome

AF:

0.0475

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.0295

AC:

4491

AN:

152330

Hom.:

Cov.:

AF XY:

0.0283

AC XY:

2109

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00825

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.0507

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0574

Gnomad4 FIN

AF:

0.0255

Gnomad4 NFE

AF:

0.0448

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0434

Hom.:

101

Bravo

AF:

0.0270

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0472

AC:

182

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0456

AC:

392

ExAC

AF:

0.0353

AC:

4285

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0459

EpiControl

AF:

0.0458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1GG

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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 19, 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

- -

Hereditary pheochromocytoma-paraganglioma

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.24

T;T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

.;N;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.20

.;N;N;N

REVEL

Benign

0.078

Sift

Benign

0.61

.;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.37

MPC

0.69

ClinPred

0.0011

GERP RS

1.6

Varity_R

0.050

gMVP

0.57

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