5-233619-C-G

Position:

• chr5-233619-C-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.1038C>G​(p.Ser346Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,646 control chromosomes in the GnomAD database, including 25,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7548 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17940 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.935

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]

ENSG00000286001 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-233619-C-G is Benign according to our data. Variant chr5-233619-C-G is described in ClinVar as [Benign]. Clinvar id is 130273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-233619-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1038C>G	p.Ser346Ser	synonymous_variant	8/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1038C>G	p.Ser346Ser	synonymous_variant	8/15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.1038C>G		non_coding_transcript_exon_variant	8/24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37835 AN: 152008 Hom.: 7523 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0820

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.241

GnomAD3 exomes AF: 0.155 AC: 39002 AN: 251450 Hom.: 4780 AF XY: 0.145 AC XY: 19766 AN XY: 135896

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.0608

Gnomad SAS exome AF: 0.0906

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.138 AC: 201643 AN: 1461520 Hom.: 17940 Cov.: 32 AF XY: 0.135 AC XY: 98314 AN XY: 727096

Gnomad4 AFR exome AF: 0.573

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.0480

Gnomad4 SAS exome AF: 0.0902

Gnomad4 FIN exome AF: 0.0883

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.249 AC: 37906 AN: 152126 Hom.: 7548 Cov.: 32 AF XY: 0.243 AC XY: 18079 AN XY: 74372

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.0886

Gnomad4 FIN AF: 0.0820

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.237

Alfa AF: 0.123 Hom.: 538

Bravo AF: 0.277

Asia WGS AF: 0.116 AC: 408 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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. -

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. -

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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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	-0.54
CADD	Benign	4.0
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1041949; hg19: chr5-233734; COSMIC: COSV53765897; COSMIC: COSV53765897;