5-230865-A-G

Position:

chr5-230865-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004168.4(SDHA):c.771-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,613,942 control chromosomes in the GnomAD database, including 633,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62026 hom., cov: 31)

Exomes 𝑓: 0.88 ( 571660 hom. )

Consequence

SDHA
NM_004168.4 intron

Scores

Splicing: ADA: 0.00001184

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.249

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:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 5-230865-A-G is Benign according to our data. Variant chr5-230865-A-G is described in ClinVar as [Benign]. Clinvar id is 259248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-230865-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 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.771-11A>G		intron_variant		ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.771-11A>G		intron_variant		1	NM_004168.4	ENSP00000264932.6		P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.771-11A>G		intron_variant				ENSP00000499215.1		A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.900

AC:

136939

AN:

152070

Hom.:

61966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.970

Gnomad AMI

AF:

0.917

Gnomad AMR

AF:

0.892

Gnomad ASJ

AF:

0.807

Gnomad EAS

AF:

0.662

Gnomad SAS

AF:

0.893

Gnomad FIN

AF:

0.922

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.880

Gnomad OTH

AF:

0.893

GnomAD3 exomes

AF:

0.877

AC:

220444

AN:

251370

Hom.:

97313

AF XY:

0.877

AC XY:

119103

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.973

Gnomad AMR exome

AF:

0.893

Gnomad ASJ exome

AF:

0.812

Gnomad EAS exome

AF:

0.659

Gnomad SAS exome

AF:

0.903

Gnomad FIN exome

AF:

0.923

Gnomad NFE exome

AF:

0.884

Gnomad OTH exome

AF:

0.869

GnomAD4 exome

AF:

0.883

AC:

1291092

AN:

1461754

Hom.:

571660

Cov.:

AF XY:

0.883

AC XY:

641980

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.972

Gnomad4 AMR exome

AF:

0.892

Gnomad4 ASJ exome

AF:

0.808

Gnomad4 EAS exome

AF:

0.680

Gnomad4 SAS exome

AF:

0.901

Gnomad4 FIN exome

AF:

0.920

Gnomad4 NFE exome

AF:

0.887

Gnomad4 OTH exome

AF:

0.873

GnomAD4 genome

AF:

0.901

AC:

137060

AN:

152188

Hom.:

62026

Cov.:

AF XY:

0.902

AC XY:

67102

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.970

Gnomad4 AMR

AF:

0.893

Gnomad4 ASJ

AF:

0.807

Gnomad4 EAS

AF:

0.662

Gnomad4 SAS

AF:

0.894

Gnomad4 FIN

AF:

0.922

Gnomad4 NFE

AF:

0.880

Gnomad4 OTH

AF:

0.891

Alfa

AF:

0.883

Hom.:

11977

Bravo

AF:

0.899

Asia WGS

AF:

0.785

AC:

2731

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

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	Feb 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex II deficiency, nuclear type 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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. -

Dilated cardiomyopathy 1GG

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2015

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. -

Neurodegeneration with ataxia and late-onset optic atrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.8

DANN

Benign

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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