rs1126417

chr5-230996-T-Cchr5-230996-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004168.4(SDHA):c.891T>C(p.Pro297=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,613,450 control chromosomes in the GnomAD database, including 449,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P297P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42249 hom., cov: 33)
  • Exomes 𝑓: 0.74 (406924 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.31

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-230996-T-C is Benign according to our data. Variant chr5-230996-T-C is described in ClinVar as [Benign]. Clinvar id is 130283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-230996-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4	c.891T>C	p.Pro297=	synonymous_variant	7/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.891T>C	p.Pro297=	synonymous_variant	7/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112600 AN: 152064 Hom.: 42215 Cov.: 33

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.737

GnomAD3 exomes AF: 0.700 AC: 175528 AN: 250646 Hom.: 63289 AF XY: 0.703 AC XY: 95344 AN XY: 135556

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.320

Gnomad SAS exome AF: 0.681

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.757

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.742 AC: 1084235 AN: 1461266 Hom.: 406924 Cov.: 53 AF XY: 0.740 AC XY: 537674 AN XY: 726970

Gnomad4 AFR exome AF: 0.784

Gnomad4 AMR exome AF: 0.659

Gnomad4 ASJ exome AF: 0.696

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.683

Gnomad4 FIN exome AF: 0.762

Gnomad4 NFE exome AF: 0.764

Gnomad4 OTH exome AF: 0.722

GnomAD4 genome AF: 0.741 AC: 112696 AN: 152184 Hom.: 42249 Cov.: 33 AF XY: 0.737 AC XY: 54854 AN XY: 74386

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.674

Gnomad4 FIN AF: 0.751

Gnomad4 NFE AF: 0.758

Gnomad4 OTH AF: 0.734

Alfa AF: 0.754 Hom.: 18654

Bravo AF: 0.735

Asia WGS AF: 0.523 AC: 1820 AN: 3478

EpiCase AF: 0.752

EpiControl AF: 0.747

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Mitochondrial complex II deficiency, nuclear type 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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. -

Neurodegeneration with ataxia and late-onset optic atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.8
Dann	Benign	0.37

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

Other links and lift over

dbSNP: rs1126417; hg19: chr5-231111; COSMIC: COSV53767683; COSMIC: COSV53767683;