rs1139424

chr5-224518-A-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.309A>G(p.Ala103=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.652

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 5-224518-A-G is Benign according to our data. Variant chr5-224518-A-G is described in ClinVar as [Benign]. Clinvar id is 130280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-224518-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SDHA	NM_004168.4	c.309A>G	p.Ala103=	synonymous_variant	3/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.309A>G	p.Ala103=	synonymous_variant	3/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36481 AN: 152022 Hom.: 6820 Cov.: 33

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

GnomAD3 exomes AF: 0.150 AC: 37476 AN: 250446 Hom.: 3993 AF XY: 0.141 AC XY: 19055 AN XY: 135416

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 SAS exome AF: 0.0894

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.: 32 AF XY: 0.126 AC XY: 90263 AN XY: 716870

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0471

Gnomad4 SAS exome AF: 0.0867

Gnomad4 FIN exome AF: 0.0878

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.240 AC: 36552 AN: 152140 Hom.: 6846 Cov.: 33 AF XY: 0.235 AC XY: 17451 AN XY: 74390

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0558

Gnomad4 SAS AF: 0.0889

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.230

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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 12, 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	4.1
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs1139424; hg19: chr5-224633; COSMIC: COSV53765839; COSMIC: COSV53765839;