NM_004168.4:c.309A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004168.4(SDHA):c.309A>G(p.Ala103Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,591,882 control chromosomes in the GnomAD database, including 19,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 6846 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12173 hom. )

Consequence

SDHA
NM_004168.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.652

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 5-224518-A-G is Benign according to our data. Variant chr5-224518-A-G is described in ClinVar as Benign. ClinVar VariationId is 130280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.652 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.309A>G	p.Ala103Ala	synonymous_variant	Exon 3 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.309A>G	p.Ala103Ala	synonymous_variant	Exon 3 of 15	1	NM_004168.4	ENSP00000264932.6		P31040-1
ENSG00000286001	ENST00000651543.1 link	n.309A>G		non_coding_transcript_exon_variant	Exon 3 of 24			ENSP00000499215.1		A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36481

AN:

152022

Hom.:

6820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.524

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.221

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.0563

Gnomad SAS

AF:

0.0886

Gnomad FIN

AF:

0.0821

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.150

AC:

37476

AN:

250446

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.160

Gnomad EAS exome

AF:

0.0603

Gnomad FIN exome

AF:

0.0856

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.128

AC:

184521

AN:

1439742

Hom.:

12173

Cov.:

AF XY:

0.126

AC XY:

90263

AN XY:

716870

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.519

AC:

16785

AN:

32346

American (AMR)

AF:

0.178

AC:

7842

AN:

44076

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

4073

AN:

25874

East Asian (EAS)

AF:

0.0471

AC:

1866

AN:

39640

South Asian (SAS)

AF:

0.0867

AC:

7436

AN:

85718

European-Finnish (FIN)

AF:

0.0878

AC:

4688

AN:

53368

Middle Eastern (MID)

AF:

0.140

AC:

633

AN:

4512

European-Non Finnish (NFE)

AF:

0.121

AC:

132398

AN:

1094712

Other (OTH)

AF:

0.148

AC:

8800

AN:

59496

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

6479

12959

19438

25918

32397

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4986

9972

14958

19944

24930

<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:

0.240

AC:

36552

AN:

152140

Hom.:

6846

Cov.:

AF XY:

0.235

AC XY:

17451

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.524

AC:

21732

AN:

41440

American (AMR)

AF:

0.220

AC:

3366

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

574

AN:

3468

East Asian (EAS)

AF:

0.0558

AC:

289

AN:

5178

South Asian (SAS)

AF:

0.0889

AC:

429

AN:

4824

European-Finnish (FIN)

AF:

0.0821

AC:

871

AN:

10612

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.124

AC:

8466

AN:

68010

Other (OTH)

AF:

0.230

AC:

484

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1165

2329

3494

4658

5823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.181

Hom.:

1597

Bravo

AF:

0.267

Asia WGS

AF:

0.114

AC:

399

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Pheochromocytoma/paraganglioma syndrome 5

Benign:2

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 is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 08, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP65+BP7 -

Nov 18, 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. -

Mitochondrial complex II deficiency, nuclear type 1

Benign:1

Jan 12, 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. -

Leigh syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.1

(source)

DANN

Benign

0.32

PhyloP100

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=86/14

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