5-53646367-A-G

Variant names:

• chr5-53646367-A-G
• rs31303
• NM_002495.4:c.312A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002495.4(NDUFS4):​c.312A>G​(p.Arg104Arg) 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:8
• Conservation: PhyloP100: 0.713
• Publications: 35 publications found

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]

NDUFS4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency, nuclear type

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.312A>G	p.Arg104Arg	synonymous_variant	Exon 3 of 5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.312A>G	p.Arg104Arg	synonymous_variant	Exon 3 of 5	1	NM_002495.4	ENSP00000296684.5

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

GnomAD2 exomes AF: 0.775 AC: 194783 AN: 251396 AF XY: 0.774

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 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

African (AFR) AF: 0.856 AC: 28643 AN: 33466

American (AMR) AF: 0.805 AC: 35991 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 19181 AN: 26126

East Asian (EAS) AF: 0.732 AC: 29054 AN: 39666

South Asian (SAS) AF: 0.778 AC: 67051 AN: 86238

European-Finnish (FIN) AF: 0.753 AC: 40199 AN: 53406

Middle Eastern (MID) AF: 0.773 AC: 4453 AN: 5758

European-Non Finnish (NFE) AF: 0.766 AC: 851542 AN: 1111442

Other (OTH) AF: 0.776 AC: 46857 AN: 60350

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

African (AFR) AF: 0.852 AC: 35359 AN: 41506

American (AMR) AF: 0.806 AC: 12304 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2553 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3961 AN: 5156

South Asian (SAS) AF: 0.775 AC: 3732 AN: 4816

European-Finnish (FIN) AF: 0.754 AC: 7969 AN: 10562

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51718 AN: 67972

Other (OTH) AF: 0.769 AC: 1626 AN: 2114

Alfa AF: 0.771 Hom.: 91191

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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 13, 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 13, 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	-0.53
CADD	Benign	9.2
DANN	Benign	0.62
PhyloP100		0.71
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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