chr5-53683151-CA-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_002495.4(NDUFS4):c.462delA(p.Lys154AsnfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,611,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

NDUFS4
NM_002495.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.689

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 Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.125 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-53683151-CA-C is Pathogenic according to our data. Variant chr5-53683151-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 40257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53683151-CA-C is described in Lovd as [Pathogenic]. Variant chr5-53683151-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4 link	c.462delA	p.Lys154AsnfsTer35	frameshift_variant	Exon 5 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.462delA	p.Lys154AsnfsTer35	frameshift_variant	Exon 5 of 5	1	NM_002495.4	ENSP00000296684.5		O43181

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250776

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1459872

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

726332

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.000307

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1

Pathogenic:2

Mar 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Feb 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19107570, 24020637, 19364667, 22326555, 33233646, 33771987, 31589614, 20818383) -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the NDUFS4 gene (p.Lys154Asnfs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the NDUFS4 protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs773369163, gnomAD 0.02%). This frameshift has been observed in individuals with Leigh syndrome (PMID: 19107570, 19364667, 20818383, 24020637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40257). Studies have shown that this frameshift alters NDUFS4 gene expression (PMID: 24020637). For these reasons, this variant has been classified as Pathogenic. -

Leigh syndrome

Pathogenic:1

Mar 03, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NDUFS4 c.462delA (p.Lys154AsnfsX35) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 8.4e-05 in 260860 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NDUFS4 causing Leigh Syndrome (8.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.462delA has been reported in the literature in multiple individuals affected with Leigh Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 19107570, 20818383, 19364667, 24020637). ClinVar contains an entry for this variant (Variation ID: 40257). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Apr 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.462delA (p.K154Nfs*35) alteration, located in exon 5 (coding exon 5) of the NDUFS4 gene, consists of a deletion of one nucleotide at position 462, causing a translational frameshift with a predicted alternate stop codon after 35 amino acids. This alteration occurs at the 3' terminus of the NDUFS4 gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 12 amino acids. This frameshift impacts the last 22 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals with Leigh syndrome in the homozygous and compound heterozygous states (Anderson, 2008; Leshinsky-Silver, 2009; Calvo, 2010; Assereto, 2014). In one family, three affected siblings were homozygous and the parents and a healthy sibling were heterozygous (Anderson, 2008). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Jul 15, 2024

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PM3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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