2-206141952-T-C

Position:

• chr2-206141952-T-C

Variant summary

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

The NM_005006.7(NDUFS1):​c.1251A>G​(p.Arg417=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,607,042 control chromosomes in the GnomAD database, including 79,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9320 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70245 hom.)
• Consequence: NDUFS1 NM_005006.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.421

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-206141952-T-C is Benign according to our data. Variant chr2-206141952-T-C is described in ClinVar as [Benign]. Clinvar id is 129695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206141952-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.421 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS1	NM_005006.7	c.1251A>G	p.Arg417=	synonymous_variant	12/19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11	c.1251A>G	p.Arg417=	synonymous_variant	12/19	1	NM_005006.7	ENSP00000233190	P1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51977 AN: 151866 Hom.: 9315 Cov.: 32

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.345

GnomAD3 exomes AF: 0.307 AC: 77088 AN: 251248 Hom.: 12294 AF XY: 0.302 AC XY: 40959 AN XY: 135796

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.244

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.307 AC: 446709 AN: 1455058 Hom.: 70245 Cov.: 32 AF XY: 0.305 AC XY: 221147 AN XY: 724276

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.347

Gnomad4 EAS exome AF: 0.214

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.342 AC: 52018 AN: 151984 Hom.: 9320 Cov.: 32 AF XY: 0.339 AC XY: 25175 AN XY: 74262

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.354

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.343

Alfa AF: 0.319 Hom.: 13378

Bravo AF: 0.348

Asia WGS AF: 0.237 AC: 824 AN: 3476

EpiCase AF: 0.326

EpiControl AF: 0.326

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Mitochondrial complex 1 deficiency, nuclear type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.70

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: rs1801318; hg19: chr2-207006676; COSMIC: COSV51910175;