rs11548670

Positions:

• chr2-206147759-A-G

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.414T>C​(p.Asp138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,942 control chromosomes in the GnomAD database, including 1,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (322 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1179 hom.)
• Consequence: NDUFS1 NM_005006.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.735

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=-0.5).
• BP6: Variant 2-206147759-A-G is Benign according to our data. Variant chr2-206147759-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.735 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS1	NM_005006.7	c.414T>C	p.Asp138=	synonymous_variant	6/19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11	c.414T>C	p.Asp138=	synonymous_variant	6/19	1	NM_005006.7	ENSP00000233190	P1

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8587 AN: 152110 Hom.: 322 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.0736

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0481 AC: 12107 AN: 251470 Hom.: 350 AF XY: 0.0478 AC XY: 6497 AN XY: 135906

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0425

Gnomad ASJ exome AF: 0.0424

Gnomad EAS exome AF: 0.0561

Gnomad SAS exome AF: 0.0616

Gnomad FIN exome AF: 0.0746

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0375 AC: 54864 AN: 1461714 Hom.: 1179 Cov.: 33 AF XY: 0.0382 AC XY: 27781 AN XY: 727176

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.0405

Gnomad4 EAS exome AF: 0.0535

Gnomad4 SAS exome AF: 0.0616

Gnomad4 FIN exome AF: 0.0730

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0564 AC: 8590 AN: 152228 Hom.: 322 Cov.: 32 AF XY: 0.0568 AC XY: 4231 AN XY: 74448

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0313

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.0646

Gnomad4 FIN AF: 0.0736

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0396 Hom.: 161

Bravo AF: 0.0546

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.0284

EpiControl AF: 0.0307

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2012	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	-	- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11548670; hg19: chr2-207012483;