5-225582-G-C

Position:

chr5-225582-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004168.4(SDHA):c.456+20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,874 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 78 hom. )

Consequence

SDHA
NM_004168.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.97

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 -16 ACMG points.

BP6

Variant 5-225582-G-C is Benign according to our data. Variant chr5-225582-G-C is described in ClinVar as [Benign]. Clinvar id is 259246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-225582-G-C is described in Lovd as [Likely_benign]. Variant chr5-225582-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00431 (656/152282) while in subpopulation SAS AF= 0.0178 (86/4826). AF 95% confidence interval is 0.0148. There are 4 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.456+20G>C		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.456+20G>C		intron_variant		1	NM_004168.4	ENSP00000264932.6		P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.456+20G>C		intron_variant				ENSP00000499215.1		A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

659

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.0263

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00691

AC:

1722

AN:

249330

Hom.:

AF XY:

0.00807

AC XY:

1093

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.000905

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0219

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00578

Gnomad OTH exome

AF:

0.00888

GnomAD4 exome

AF:

0.00685

AC:

10006

AN:

1461592

Hom.:

Cov.:

AF XY:

0.00731

AC XY:

5316

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.0245

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0206

Gnomad4 FIN exome

AF:

0.00169

Gnomad4 NFE exome

AF:

0.00622

Gnomad4 OTH exome

AF:

0.00671

GnomAD4 genome

AF:

0.00431

AC:

656

AN:

152282

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.0263

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00553

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00783

Hom.:

Bravo

AF:

0.00414

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

DANN

Benign

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.46

Position offset: 48

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