rs747359752

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_002495.4(NDUFS4):c.355G>C(p.Asp119His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D119G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NDUFS4
NM_002495.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.55

Publications

11 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: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 5-53658555-G-C is Pathogenic according to our data. Variant chr5-53658555-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 587577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4 link	c.355G>C	p.Asp119His	missense_variant	Exon 4 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.355G>C	p.Asp119His	missense_variant	Exon 4 of 5	1	NM_002495.4	ENSP00000296684.5		O43181

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251172

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460850

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111320

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1

Pathogenic:2

Genomics, Clalit Research Institute, Clalit Health Care

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inheritance: The variant was identified in the Homozygous state in the sample. Frequency: The variant is rare, observed in 2 alleles out of 251,172 (0.001%) in the gnomAD reference population dataset. (PM2_support) Allelic data: This variant was previously reported in trans with a pathogenic variant or in a homozygous state (PMID: 31386302‚ 31292494, Clalit). (PM3_strong) Prediction tools: REVEL predicts a deleterious effect on the gene or gene product (score 0.88). (PP3_moderate) Phenotype: The patient's phenotype or family history is highly specific for a disease with a single genetic etiology. (PP4) Clinical evidence: This variant has previously been described in ClinVar (VCV587577) with the following classifications: LP (5). Sources: This variant has been previously described in several publications (see PMID: 19364667, 31386302, and 31292494). Notably, these studies separately described two patients with the clinical diagnosis of Leigh syndrome who were carriers of this variant either in the heterozygous or homozygous state. Sage-Schwaede, et al., moreover discussed a potential pharmacological intervention. Taken together, we interpret this variant as pathogenic (pm2_support, pm3_strong, pp3_moderate, pp4). -

Oct 30, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leigh syndrome

Pathogenic:1

Sep 01, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial complex I deficiency

Pathogenic:1

Sep 01, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jan 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 119 of the NDUFS4 protein (p.Asp119His). This variant is present in population databases (rs747359752, gnomAD 0.01%). This missense change has been observed in individual(s) with Leigh syndrome (PMID: 19364667, 31386302). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 587577). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFS4 function (PMID: 22326555). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

PhyloP100

6.6

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

1.0

MutPred

0.98

Gain of catalytic residue at L121 (P = 0.0594);

MVP

0.97

MPC

0.21

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.84

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over