rs34504623

Positions:

chr5-254521-C-T

Variant summary

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

The NM_004168.4(SDHA):c.1908+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,540,732 control chromosomes in the GnomAD database, including 9,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 680 hom., cov: 28)

Exomes 𝑓: 0.11 ( 9236 hom. )

Consequence

SDHA
NM_004168.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.98

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=-1.01).

BP6

Variant 5-254521-C-T is Benign according to our data. Variant chr5-254521-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-254521-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 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.1908+15C>T		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.1908+15C>T		intron_variant		1	NM_004168.4	ENSP00000264932.6		P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*641+15C>T		intron_variant				ENSP00000499215.1		A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.0791

AC:

11899

AN:

150508

Hom.:

680

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.0706

Gnomad AMR

AF:

0.0692

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.00156

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.0822

GnomAD3 exomes

AF:

0.0783

AC:

12239

AN:

156268

Hom.:

644

AF XY:

0.0766

AC XY:

6343

AN XY:

82858

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.0601

Gnomad ASJ exome

AF:

0.0962

Gnomad EAS exome

AF:

0.000176

Gnomad SAS exome

AF:

0.0151

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0977

GnomAD4 exome

AF:

0.108

AC:

150186

AN:

1390108

Hom.:

9236

Cov.:

AF XY:

0.105

AC XY:

72411

AN XY:

686536

show subpopulations

Gnomad4 AFR exome

AF:

0.0176

Gnomad4 AMR exome

AF:

0.0643

Gnomad4 ASJ exome

AF:

0.100

Gnomad4 EAS exome

AF:

0.000139

Gnomad4 SAS exome

AF:

0.0167

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.0999

GnomAD4 genome

AF:

0.0790

AC:

11895

AN:

150624

Hom.:

680

Cov.:

AF XY:

0.0762

AC XY:

5605

AN XY:

73572

show subpopulations

Gnomad4 AFR

AF:

0.0213

Gnomad4 AMR

AF:

0.0691

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.00157

Gnomad4 SAS

AF:

0.0157

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.0813

Alfa

AF:

0.0938

Hom.:

125

Bravo

AF:

0.0746

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2019	- -

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. -

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

May 14, 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. -

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

-1.0

CADD

Benign

0.086

DANN

Benign

0.34

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