rs104893898

Positions:

• chr5-53646371-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000296684.10(NDUFS4):​c.316C>T​(p.Arg106Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,482 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NDUFS4 ENST00000296684.10 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.54

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-53646371-C-T is Pathogenic according to our data. Variant chr5-53646371-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.316C>T	p.Arg106Ter	stop_gained	3/5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.316C>T	p.Arg106Ter	stop_gained	3/5	1	NM_002495.4	ENSP00000296684	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461482 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 18, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with mitochondrial complex I deficiency (PMID: 10944442). Functional studies have shown the presence of this variant results in a reduction of complex I enzymatic activity in skeletal muscle (PMID: 10944442). The c.316C>T (p.Arg106Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004 % (1/251396) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.316C>T (p.Arg106Ter) variant is classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2023	This sequence change creates a premature translational stop signal (p.Arg106*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFS4 are known to be pathogenic (PMID: 10944442, 16213125). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 10944442). ClinVar contains an entry for this variant (Variation ID: 6889). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2022	Functional studies conducted in patient cells demonstrate R106* exhibits morphogenesis defects as neurite outgrowth was decreased in immature neurons expressing the variant compared to wild type neural progenitor cells (Inak et al., 2021); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22033105, 10944442, 32860008, 33771987) -

Leigh syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 31, 2022

Variant summary: NDUFS4 c.316C>T (p.Arg106X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). c.316C>T has been reported in the literature in multiple individuals affected with NADH-ubiquinone oxidoreductase (complex I) deficiency or combined complex I and III deficiency (Budde_2000, Voets_2012, Haack_2012). These data indicate that the variant is very likely to be associated with disease. In addition, this variant results in impaired cytosolic Ca2+ handling in complex I-deficient fibroblasts (Visch_2004, Voets_2012). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mitochondrial complex I deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		1.9
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

Other links and lift over

dbSNP: rs104893898; hg19: chr5-52942201;