rs31303

chr5-53646367-A-Gchr5-53646367-A-T

Variant summary

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

The NM_002495.4(NDUFS4):c.312A>G(p.Arg104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,250 control chromosomes in the GnomAD database, including 479,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47554 hom., cov: 31)
  • Exomes 𝑓: 0.77 (432296 hom.)
• Consequence: NDUFS4 NM_002495.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.713

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-53646367-A-G is Benign according to our data. Variant chr5-53646367-A-G is described in ClinVar as [Benign]. Clinvar id is 129701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53646367-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.713 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS4	NM_002495.4	c.312A>G	p.Arg104=	synonymous_variant	3/5	ENST00000296684.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS4	ENST00000296684.10	c.312A>G	p.Arg104=	synonymous_variant	3/5	1	NM_002495.4	P1

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119917 AN: 151958 Hom.: 47509 Cov.: 31

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.772

GnomAD3 exomes AF: 0.775 AC: 194783 AN: 251396 Hom.: 75681 AF XY: 0.774 AC XY: 105129 AN XY: 135870

Gnomad AFR exome AF: 0.856

Gnomad AMR exome AF: 0.804

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.773

Gnomad SAS exome AF: 0.776

Gnomad FIN exome AF: 0.754

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.769 AC: 1122971 AN: 1461174 Hom.: 432296 Cov.: 49 AF XY: 0.768 AC XY: 558472 AN XY: 726924

Gnomad4 AFR exome AF: 0.856

Gnomad4 AMR exome AF: 0.805

Gnomad4 ASJ exome AF: 0.734

Gnomad4 EAS exome AF: 0.732

Gnomad4 SAS exome AF: 0.778

Gnomad4 FIN exome AF: 0.753

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.776

GnomAD4 genome AF: 0.789 AC: 120019 AN: 152076 Hom.: 47554 Cov.: 31 AF XY: 0.790 AC XY: 58678 AN XY: 74320

Gnomad4 AFR AF: 0.852

Gnomad4 AMR AF: 0.806

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.768

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.754

Gnomad4 NFE AF: 0.761

Gnomad4 OTH AF: 0.769

Alfa AF: 0.769 Hom.: 74545

Bravo AF: 0.794

Asia WGS AF: 0.777 AC: 2702 AN: 3478

EpiCase AF: 0.757

EpiControl AF: 0.763

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not specified Benign:1

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. -

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	-0.53
Cadd	Benign	9.2
Dann	Benign	0.62

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: rs31303; hg19: chr5-52942197; COSMIC: COSV57019407;