Variant 5-251354-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004168.4(SDHA):c.1680G>A(p.Thr560=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,609,722 control chromosomes in the GnomAD database, including 23,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 6843 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17064 hom. )

Consequence

SDHA
NM_004168.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.40

Variant links:

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]

SDHA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 5-251354-G-A is Benign according to our data. Variant chr5-251354-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-251354-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1680G>A	p.Thr560=	synonymous_variant	13/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1680G>A	p.Thr560=	synonymous_variant	13/15	1	NM_004168.4	ENSP00000264932	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36411

AN:

151798

Hom.:

6815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0555

Gnomad SAS

AF:

0.0880

Gnomad FIN

AF:

0.0815

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.233

GnomAD3 exomes

AF:

0.145

AC:

35830

AN:

246644

Hom.:

3797

AF XY:

0.138

AC XY:

18427

AN XY:

133840

show subpopulations

Gnomad AFR exome

AF:

0.529

Gnomad AMR exome

AF:

0.182

Gnomad ASJ exome

AF:

0.160

Gnomad EAS exome

AF:

0.0586

Gnomad SAS exome

AF:

0.0885

Gnomad FIN exome

AF:

0.0843

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.136

AC:

198179

AN:

1457808

Hom.:

17064

Cov.:

AF XY:

0.133

AC XY:

96663

AN XY:

725258

show subpopulations

Gnomad4 AFR exome

AF:

0.543

Gnomad4 AMR exome

AF:

0.185

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.0479

Gnomad4 SAS exome

AF:

0.0895

Gnomad4 FIN exome

AF:

0.0879

Gnomad4 NFE exome

AF:

0.129

Gnomad4 OTH exome

AF:

0.155

GnomAD4 genome

AF:

0.240

AC:

36484

AN:

151914

Hom.:

6843

Cov.:

AF XY:

0.234

AC XY:

17388

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.525

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.0550

Gnomad4 SAS

AF:

0.0882

Gnomad4 FIN

AF:

0.0815

Gnomad4 NFE

AF:

0.124

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.157

Hom.:

902

Bravo

AF:

0.267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-	- -

Mitochondrial complex II deficiency, nuclear type 1

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

- -

Leigh syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.5

DANN

Benign

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over