rs35502109

Positions:

• chr5-251063-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004168.4(SDHA):​c.1623G>A​(p.Lys541Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,612,024 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 0.230

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-251063-G-A is Benign according to our data. Variant chr5-251063-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252905.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=5}. Variant chr5-251063-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (328/152330) while in subpopulation AMR AF= 0.0049 (75/15308). AF 95% confidence interval is 0.00401. There are 3 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1623G>A	p.Lys541Lys	synonymous_variant	12/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1623G>A	p.Lys541Lys	synonymous_variant	12/15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*356G>A		non_coding_transcript_exon_variant	11/24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*356G>A		3_prime_UTR_variant	11/24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251140 Hom.: 0 AF XY: 0.00238 AC XY: 323 AN XY: 135720

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00218 AC: 3188 AN: 1459694 Hom.: 11 Cov.: 31 AF XY: 0.00230 AC XY: 1667 AN XY: 726156

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74500

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00280 Hom.: 2

Bravo AF: 0.00218

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00367

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SDHA: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	This variant is associated with the following publications: (PMID: 17298551, 23666964) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2014	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 27, 2021	- -

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

- -

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.2
DANN	Benign	0.32
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: rs35502109; hg19: chr5-251178;