rs121964845
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PP3_ModeratePP5_Very_StrongBS1_Supporting
The NM_000365.6(TPI1):c.315G>C(p.Glu105Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,110 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 (★★).
Frequency
Consequence
NM_000365.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPI1 | NM_000365.6 | c.315G>C | p.Glu105Asp | missense_variant | Exon 3 of 7 | ENST00000396705.10 | NP_000356.1 | |
TPI1 | NM_001159287.1 | c.426G>C | p.Glu142Asp | missense_variant | Exon 3 of 7 | NP_001152759.1 | ||
TPI1 | NM_001258026.2 | c.69G>C | p.Glu23Asp | missense_variant | Exon 3 of 7 | NP_001244955.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000755 AC: 19AN: 251496Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135922
GnomAD4 exome AF: 0.000269 AC: 393AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.000275 AC XY: 200AN XY: 727240
GnomAD4 genome AF: 0.000105 AC: 16AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74376
ClinVar
Submissions by phenotype
Triosephosphate isomerase deficiency Pathogenic:6
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PS3,PM3,PP3 -
The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3. -
not provided Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the TPI1 protein (p.Glu105Asp). This variant is present in population databases (rs121964845, gnomAD 0.01%). This missense change has been observed in individual(s) with triosephosphate isomerase deficiency (PMID: 2876430, 10910933, 24192681). ClinVar contains an entry for this variant (Variation ID: 12468). 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 TPI1 function (PMID: 17183658). For these reasons, this variant has been classified as Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at