rs587776949

Positions:

• chr5-53683151-CA-C
• chr5-53683151-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002495.4(NDUFS4):​c.462del​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.689

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]

ACMG classification

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 0.131 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/exons	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.462del	p.Lys154AsnfsTer35	frameshift_variant	5/5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.462del	p.Lys154AsnfsTer35	frameshift_variant	5/5	1	NM_002495.4	ENSP00000296684	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151922 Hom.: 0 Cov.: 32

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: 17 AN: 250776 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135496

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: 78 AN: 1459872 Hom.: 0 Cov.: 31 AF XY: 0.0000620 AC XY: 45 AN XY: 726332

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: 4 AN: 151922 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74204

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.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2023	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) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2021

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. -

Leigh syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 18, 2016

Variant summary: The NDUFS4 c.462delA (p.Lys154AsnfsX35) variant causes a frameshift mutation resulting in the elongation of the NDUFS4 protein by 12 amino acids. A functional study indicates that the mutation causes a reduction of the transcript levels by nonsense-mediated decay (NMD)(Assereto_2014). The variant of itnerest was observed in controls with an allele frequency of 14/131308, which does not exceed the estimated maximal expected allele frequency of a pathogenic NDUFS4 variant (0.00125). This variant has been reported in multiple LS patients both as homozygotes and compound heterozygotes. In addition, clinical diagnostic laboratory/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587776949; hg19: chr5-52978981;