Variant 5-53560674-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002495.4(NDUFS4):c.12G>C(p.Val4=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0920

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
NDUFS4	NM_002495.4 linkuse as main transcript	c.12G>C	p.Val4=	synonymous_variant	1/5	ENST00000296684.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS4	ENST00000296684.10 linkuse as main transcript	c.12G>C	p.Val4=	synonymous_variant	1/5	1	NM_002495.4	P1

Frequencies

GnomAD3 genomes

AF:

0.656

AC:

99763

AN:

152086

Hom.:

33446

Cov.:

show subpopulations

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

show subpopulations

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

show subpopulations

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.:

AF XY:

0.656

AC XY:

48782

AN XY:

74412

show subpopulations

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

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 12, 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 12, 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

-0.45

CADD

Benign

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

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