5-223531-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:18

Conservation

PhyloP100: 2.74

Publications

26 publications found

Variant links:

COSMIC-nc: COSV53772162

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 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
pheochromocytoma/paraganglioma syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial complex II deficiency, nuclear type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
neurodegeneration with ataxia and late-onset optic atrophy
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
gastrointestinal stromal tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex II deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1GG
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 224957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.113A>T	p.Asp38Val	missense_variant	Exon 2 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11 link	c.113A>T	p.Asp38Val	missense_variant	Exon 2 of 15	1	NM_004168.4	ENSP00000264932.6		P31040-1
ENSG00000286001	ENST00000651543.1 link	n.113A>T		non_coding_transcript_exon_variant	Exon 2 of 24			ENSP00000499215.1		A0A494C1T6

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

GnomAD2 exomes

AF:

0.0351

AC:

8822

AN:

251180

AF XY:

0.0381

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 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

African (AFR)

AF:

0.00547

AC:

183

AN:

33470

American (AMR)

AF:

0.0144

AC:

645

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0503

AC:

1314

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0604

AC:

5205

AN:

86234

European-Finnish (FIN)

AF:

0.0243

AC:

1298

AN:

53418

Middle Eastern (MID)

AF:

0.0437

AC:

252

AN:

5762

European-Non Finnish (NFE)

AF:

0.0475

AC:

52761

AN:

1111366

Other (OTH)

AF:

0.0395

AC:

2385

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3054

6109

9163

12218

15272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1938

3876

5814

7752

9690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0295

AC:

4491

AN:

152330

Hom.:

Cov.:

AF XY:

0.0283

AC XY:

2109

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00825

AC:

343

AN:

41576

American (AMR)

AF:

0.0195

AC:

299

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

176

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5194

South Asian (SAS)

AF:

0.0574

AC:

277

AN:

4828

European-Finnish (FIN)

AF:

0.0255

AC:

271

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0448

AC:

3046

AN:

68032

Other (OTH)

AF:

0.0331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

220

441

661

882

1102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pheochromocytoma/paraganglioma syndrome 5

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 18, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BS2+BP4+BP6 -

Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Leigh syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dilated cardiomyopathy 1GG

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Dec 03, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

2.7

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over