rs2279516

Variant names:

• chr5-53560674-G-C
• rs2279516
• NM_002495.4:c.12G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-53560674-G-C
• chr5-53560674-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002495.4(NDUFS4):​c.12G>C​(p.Val4Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,614,084 control chromosomes in the GnomAD database, including 303,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33491 hom., cov: 34)
  • Exomes 𝑓: 0.61 (269796 hom.)
• Consequence: NDUFS4 NM_002495.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0920

Genes affected

NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-53560674-G-C is Benign according to our data. Variant chr5-53560674-G-C is described in ClinVar as [Benign]. Clinvar id is 129699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53560674-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.12G>C	p.Val4Val	synonymous_variant	Exon 1 of 5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.12G>C	p.Val4Val	synonymous_variant	Exon 1 of 5	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99763 AN: 152086 Hom.: 33446 Cov.: 34

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.631 AC: 158557 AN: 251448 Hom.: 50674 AF XY: 0.625 AC XY: 84936 AN XY: 135892

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.625

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.594

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.605 AC: 885137 AN: 1461880 Hom.: 269796 Cov.: 124 AF XY: 0.605 AC XY: 440076 AN XY: 727248

Gnomad4 AFR exome AF: 0.812

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.631

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.612

GnomAD4 genome AF: 0.656 AC: 99861 AN: 152204 Hom.: 33491 Cov.: 34 AF XY: 0.656 AC XY: 48782 AN XY: 74412

Gnomad4 AFR AF: 0.802

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.576

Gnomad4 NFE AF: 0.589

Gnomad4 OTH AF: 0.633

Alfa AF: 0.615 Hom.: 9434

Bravo AF: 0.668

Asia WGS AF: 0.626 AC: 2177 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.599

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Leigh syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.45
CADD	Benign	10
DANN	Benign	0.78
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: rs2279516; hg19: chr5-52856504; COSMIC: COSV57018729; COSMIC: COSV57018729;