rs144252500

Variant names:

• chr5-233583-G-A
• rs144252500
• NM_004168.4:c.1002G>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.1002G>A​(p.Ala334Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,184 control chromosomes in the GnomAD database, including 2 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 0.00073 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -2.16

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=-0.54).
• BP6: Variant 5-233583-G-A is Benign according to our data. Variant chr5-233583-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252904.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=2}. Variant chr5-233583-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000729 (111/152328) while in subpopulation NFE AF= 0.00134 (91/68032). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1002G>A	p.Ala334Ala	synonymous_variant	Exon 8 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1002G>A	p.Ala334Ala	synonymous_variant	Exon 8 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.1002G>A		non_coding_transcript_exon_variant	Exon 8 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000835 AC: 210 AN: 251492 Hom.: 0 AF XY: 0.000927 AC XY: 126 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00107 AC: 1563 AN: 1461856 Hom.: 2 Cov.: 32 AF XY: 0.00110 AC XY: 799 AN XY: 727234

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74486

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000991 Hom.: 0

Bravo AF: 0.000771

EpiCase AF: 0.00147

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Aug 11, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23666964) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHA: BP4, BP7 -

Hereditary cancer-predisposing syndrome Benign:2

Mar 29, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 06, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 5 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SDHA-related disorder Benign:1

Sep 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pheochromocytoma-paraganglioma Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.54
CADD	Benign	0.13
DANN	Benign	0.72

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: rs144252500; hg19: chr5-233698; COSMIC: COSV99371911; COSMIC: COSV99371911;