chr12-57796539-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_005726.6(TSFM):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,466,820 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 (★★).
Frequency
Consequence
NM_005726.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSFM | NM_005726.6 | c.934C>T | p.Arg312Trp | missense_variant | Exon 6 of 6 | ENST00000652027.2 | NP_005717.3 | |
TSFM | NM_001172696.2 | c.997C>T | p.Arg333Trp | missense_variant | Exon 7 of 7 | NP_001166167.1 | ||
TSFM | NM_001172695.2 | c.*342C>T | 3_prime_UTR_variant | Exon 5 of 5 | NP_001166166.1 | |||
TSFM | NM_001172697.2 | c.571+3466C>T | intron_variant | Intron 5 of 5 | NP_001166168.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151978Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000312 AC: 41AN: 1314842Hom.: 0 Cov.: 31 AF XY: 0.0000375 AC XY: 24AN XY: 639898
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151978Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74198
ClinVar
Submissions by phenotype
Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 Pathogenic:5
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Variant summary: TSFM c.997C>T (p.Arg333Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1466820 control chromosomes (gnomAD database v4). c.997C>T has been reported in the literature in multiple individuals affected with Combined Oxidative Phosphorylation Deficiency 3 (e.g. Calvo_2012, Smeitink_2006). 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 decreased protein level and reduction of assembled mitochondrial complexes I, IV and V (Smeitink_2006). The following publications have been ascertained in the context of this evaluation (PMID: 22277967, 17033963). ClinVar contains an entry for this variant (Variation ID: 5379). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 3 (COXPD3) (MIM#610505). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in a homozygous state in more than five patients with COXPD3 (ClinVar, HGMD, PMID: 17033963, PMID: 31267352). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies in patient cells demonstrated decreased protein levels as well as a reduction in assembled mitochondrial complexes I, IV and V (PMID: 17033963). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Inborn genetic diseases Pathogenic:1
The c.997C>T (p.R333W) alteration is located in coding exon 7 of the TSFM gene. This alteration results from a C to T substitution at nucleotide position 997, causing the arginine (R) at amino acid position 333 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the c.997C>T alteration was observed in 0.0015% (3/201,630) total alleles studied, with a frequency of 0.004% (1/23,492) in the African subpopulation. This alteration was reported homozygous in multiple unrelated patients with severe combined oxidative phosphorylation deficiency, born to consanguineous parents (Smeitink, 2006; Smits, 2011; Calvo, 2012; Shamseldin, 2012; Vedrenne, 2012). This amino acid position is highly conserved in available vertebrate species. The p.R333 amino acid is located in an evolutionarily conserved site in a subdomain of EFTs that interacts with EFTu. Molecular modeling predicted that the mutation disrupts local subdomain structure and the dimerization interface (Smeitink, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the TSFM protein (p.Arg333Trp). 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 missense change has been observed in individual(s) with mitochondrial disorders (PMID: 17033963, 21741925, 22277967). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg312Trp. ClinVar contains an entry for this variant (Variation ID: 5379). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TSFM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TSFM function (PMID: 20435138). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at