rs31304

Variant names:

• chr5-53646253-A-C
• rs31304
• NM_002495.4:c.198A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-53646253-A-C
• chr5-53646253-A-T

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.198A>C​(p.Gly66Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,611,208 control chromosomes in the GnomAD database, including 746,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G66G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (70618 hom., cov: 29)
  • Exomes 𝑓: 0.96 (675896 hom.)
• Consequence: NDUFS4 NM_002495.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.697
• Publications: 28 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=-0.84).
• BP6: Variant 5-53646253-A-C is Benign according to our data. Variant chr5-53646253-A-C is described in ClinVar as Benign. ClinVar VariationId is 129700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.697 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.198A>C	p.Gly66Gly	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.198A>C	p.Gly66Gly	synonymous_variant	Exon 3 of 5	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.964 AC: 146398 AN: 151912 Hom.: 70570 Cov.: 29

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.966

Gnomad OTH AF: 0.959

GnomAD2 exomes AF: 0.955 AC: 238506 AN: 249666 AF XY: 0.954

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.946

Gnomad EAS exome AF: 0.853

Gnomad FIN exome AF: 0.944

Gnomad NFE exome AF: 0.966

Gnomad OTH exome AF: 0.953

GnomAD4 exome AF: 0.962 AC: 1404023 AN: 1459180 Hom.: 675896 Cov.: 42 AF XY: 0.962 AC XY: 698135 AN XY: 726006

African (AFR) AF: 0.975 AC: 32557 AN: 33402

American (AMR) AF: 0.984 AC: 43927 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 24675 AN: 26102

East Asian (EAS) AF: 0.852 AC: 33719 AN: 39590

South Asian (SAS) AF: 0.946 AC: 81450 AN: 86114

European-Finnish (FIN) AF: 0.942 AC: 50244 AN: 53340

Middle Eastern (MID) AF: 0.970 AC: 5583 AN: 5758

European-Non Finnish (NFE) AF: 0.968 AC: 1074150 AN: 1109946

Other (OTH) AF: 0.958 AC: 57718 AN: 60270

GnomAD4 genome AF: 0.964 AC: 146502 AN: 152028 Hom.: 70618 Cov.: 29 AF XY: 0.962 AC XY: 71475 AN XY: 74284

African (AFR) AF: 0.975 AC: 40456 AN: 41486

American (AMR) AF: 0.978 AC: 14933 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3285 AN: 3466

East Asian (EAS) AF: 0.861 AC: 4436 AN: 5152

South Asian (SAS) AF: 0.947 AC: 4557 AN: 4810

European-Finnish (FIN) AF: 0.948 AC: 10006 AN: 10560

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.966 AC: 65654 AN: 67980

Other (OTH) AF: 0.954 AC: 2011 AN: 2108

Alfa AF: 0.967 Hom.: 132534

Bravo AF: 0.966

Asia WGS AF: 0.898 AC: 3123 AN: 3478

EpiCase AF: 0.966

EpiControl AF: 0.967

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not specified Benign:2

Sep 17, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NDUFS4 c.198A>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.96 in 275374 control chromosomes, suggesting that it is the major allele (the variant most commonly observed in the general population), therefore is benign. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

-

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:2

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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.20
DANN	Benign	0.59
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs31304; hg19: chr5-52942083; COSMIC: COSV57019395;