rs2279516

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002495.4(NDUFS4):c.12G>C(p.Val4Val) 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:8

Conservation

PhyloP100: 0.0920

Publications

33 publications found

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 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

NDUFS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4 link	c.12G>C	p.Val4Val	synonymous_variant	Exon 1 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.12G>C	p.Val4Val	synonymous_variant	Exon 1 of 5	1	NM_002495.4	ENSP00000296684.5		O43181

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

GnomAD2 exomes

AF:

0.631

AC:

158557

AN:

251448

AF XY:

0.625

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 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

African (AFR)

AF:

0.812

AC:

27202

AN:

33480

American (AMR)

AF:

0.694

AC:

31058

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

16488

AN:

26136

East Asian (EAS)

AF:

0.585

AC:

23215

AN:

39700

South Asian (SAS)

AF:

0.633

AC:

54617

AN:

86258

European-Finnish (FIN)

AF:

0.581

AC:

31052

AN:

53416

Middle Eastern (MID)

AF:

0.602

AC:

3471

AN:

5768

European-Non Finnish (NFE)

AF:

0.594

AC:

661066

AN:

1112006

Other (OTH)

AF:

0.612

AC:

36968

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

27913

55825

83738

111650

139563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18190

36380

54570

72760

90950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.656

AC:

99861

AN:

152204

Hom.:

33491

Cov.:

AF XY:

0.656

AC XY:

48782

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.802

AC:

33332

AN:

41550

American (AMR)

AF:

0.661

AC:

10112

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

2216

AN:

3470

East Asian (EAS)

AF:

0.614

AC:

3170

AN:

5166

South Asian (SAS)

AF:

0.630

AC:

3040

AN:

4826

European-Finnish (FIN)

AF:

0.576

AC:

6095

AN:

10590

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.589

AC:

40040

AN:

67996

Other (OTH)

AF:

0.633

AC:

1337

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1776

3552

5329

7105

8881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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 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. -

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 12, 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

-0.45

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.092

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over