5-235249-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004168.4(SDHA):c.1170C>T(p.Phe390=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,613,954 control chromosomes in the GnomAD database, including 4,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (2275 hom., cov: 32)
  • Exomes 𝑓: 0.012 (2135 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.825

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-235249-C-T is Benign according to our data. Variant chr5-235249-C-T is described in ClinVar as [Benign]. Clinvar id is 130274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-235249-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.825 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4	c.1170C>T	p.Phe390=	synonymous_variant	9/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.1170C>T	p.Phe390=	synonymous_variant	9/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14561 AN: 152084 Hom.: 2267 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.0759

GnomAD3 exomes AF: 0.0274 AC: 6884 AN: 251358 Hom.: 950 AF XY: 0.0208 AC XY: 2829 AN XY: 135844

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0115 AC: 16827 AN: 1461752 Hom.: 2135 Cov.: 31 AF XY: 0.0102 AC XY: 7420 AN XY: 727174

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0959 AC: 14594 AN: 152202 Hom.: 2275 Cov.: 32 AF XY: 0.0923 AC XY: 6866 AN XY: 74424

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.0448

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.0751

Alfa AF: 0.0465 Hom.: 467

Bravo AF: 0.111

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00421

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2019	- -

Mitochondrial complex II deficiency, nuclear type 1 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.2
Dann	Benign	0.60

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: rs35277230; hg19: chr5-235364; COSMIC: COSV53766538; COSMIC: COSV53766538;