5-254484-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.1886A>T(p.Tyr629Phe) variant causes a missense change. The variant allele was found at a frequency of 0.145 in 1,571,694 control chromosomes in the GnomAD database, including 22,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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. Y629C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 6369 hom., cov: 28)

Exomes 𝑓: 0.14 ( 16494 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.37

Publications

30 publications found

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 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=0.008063376).

BP6

Variant 5-254484-A-T is Benign according to our data. Variant chr5-254484-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.1886A>T	p.Tyr629Phe	missense_variant	Exon 14 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SDHA	ENST00000264932.11 link	c.1886A>T	p.Tyr629Phe	missense_variant	Exon 14 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1 link	n.*619A>T		non_coding_transcript_exon_variant	Exon 13 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1 link	n.*619A>T		3_prime_UTR_variant	Exon 13 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35181

AN:

150204

Hom.:

6344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.515

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0548

Gnomad SAS

AF:

0.0855

Gnomad FIN

AF:

0.0806

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.230

GnomAD2 exomes

AF:

0.143

AC:

23869

AN:

166952

AF XY:

0.136

show subpopulations

Gnomad AFR exome

AF:

0.532

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.0578

Gnomad FIN exome

AF:

0.0839

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.135

AC:

192508

AN:

1421374

Hom.:

16494

Cov.:

AF XY:

0.133

AC XY:

93390

AN XY:

703670

show subpopulations

African (AFR)

AF:

0.539

AC:

17377

AN:

32234

American (AMR)

AF:

0.186

AC:

7353

AN:

39568

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

4137

AN:

25338

East Asian (EAS)

AF:

0.0463

AC:

1777

AN:

38364

South Asian (SAS)

AF:

0.0890

AC:

7234

AN:

81260

European-Finnish (FIN)

AF:

0.0863

AC:

4389

AN:

50884

Middle Eastern (MID)

AF:

0.151

AC:

619

AN:

4112

European-Non Finnish (NFE)

AF:

0.129

AC:

140557

AN:

1090906

Other (OTH)

AF:

0.154

AC:

9065

AN:

58708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

9154

18308

27462

36616

45770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5334

10668

16002

21336

26670

<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:

0.235

AC:

35251

AN:

150320

Hom.:

6369

Cov.:

AF XY:

0.228

AC XY:

16754

AN XY:

73434

show subpopulations

African (AFR)

AF:

0.515

AC:

20681

AN:

40150

American (AMR)

AF:

0.217

AC:

3289

AN:

15158

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

571

AN:

3466

East Asian (EAS)

AF:

0.0543

AC:

279

AN:

5136

South Asian (SAS)

AF:

0.0857

AC:

411

AN:

4794

European-Finnish (FIN)

AF:

0.0806

AC:

852

AN:

10574

Middle Eastern (MID)

AF:

0.205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.123

AC:

8364

AN:

67756

Other (OTH)

AF:

0.226

AC:

474

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

1038

2076

3115

4153

5191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.102

Hom.:

225

ESP6500AA

AF:

0.191

AC:

788

ESP6500EA

AF:

0.0448

AC:

381

ExAC

AF:

0.0895

AC:

10074

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

- -

Mar 11, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17298551, 28724664) -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 28, 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. -

Jan 08, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP6 -

Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leigh syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.24

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.1

PhyloP100

4.4

PROVEAN

Benign

-0.31

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

MutPred

0.45

Loss of MoRF binding (P = 0.0726);

ClinPred

0.0098

GERP RS

2.9

Varity_R

0.34

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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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