Genetic Variant NM_002495.4:c.312A>G (chr5-53646367-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.713

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4 link	c.312A>G	p.Arg104Arg	synonymous_variant	Exon 3 of 5	ENST00000296684.10	NP_002486.1	O43181A0A0S2Z433

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10 link	c.312A>G	p.Arg104Arg	synonymous_variant	Exon 3 of 5	1	NM_002495.4	ENSP00000296684.5		O43181

Frequencies

GnomAD3 genomes

AF:

0.789

AC:

119917

AN:

151958

Hom.:

47509

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.768

AC XY:

558472

AN XY:

726924

show subpopulations

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.:

AF XY:

0.790

AC XY:

58678

AN XY:

74320

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over