rs6555055

chr5-226045-A-Cchr5-226045-A-Gchr5-226045-A-T

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.619A>C(p.Arg207=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,886 control chromosomes in the GnomAD database, including 24,113 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R207?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.24 (6866 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17247 hom.)
• Consequence: SDHA NM_004168.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006783
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.85

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=-0.62).
• BP6: Variant 5-226045-A-C is Benign according to our data. Variant chr5-226045-A-C is described in ClinVar as [Benign]. Clinvar id is 130281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-226045-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.85 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.619A>C	p.Arg207=	splice_region_variant, synonymous_variant	5/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.619A>C	p.Arg207=	splice_region_variant, synonymous_variant	5/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36522 AN: 152030 Hom.: 6839 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.152 AC: 38252 AN: 251138 Hom.: 4448 AF XY: 0.143 AC XY: 19438 AN XY: 135790

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0606

Gnomad SAS exome AF: 0.0905

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.137 AC: 200071 AN: 1461738 Hom.: 17247 Cov.: 33 AF XY: 0.134 AC XY: 97589 AN XY: 727168

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.0480

Gnomad4 SAS exome AF: 0.0901

Gnomad4 FIN exome AF: 0.0886

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.241 AC: 36594 AN: 152148 Hom.: 6866 Cov.: 33 AF XY: 0.235 AC XY: 17458 AN XY: 74390

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0553

Gnomad4 SAS AF: 0.0886

Gnomad4 FIN AF: 0.0823

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.229

Alfa AF: 0.151 Hom.: 4441

Bravo AF: 0.267

Asia WGS AF: 0.114 AC: 400 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	-0.62
Cadd	Benign	13
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0
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: rs6555055; hg19: chr5-226160; COSMIC: COSV53765861; COSMIC: COSV53765861;