2-70212730-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_022173.4(TIA1):c.1150G>A(p.Glu384Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022173.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251450Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135894
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1459788Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9AN XY: 726350
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:5
The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. The variant is a common founder associated with Welander distal myopathy originating from Finland and Sweden (PMID: 23348830, 23401021). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23401021, 28817800) -
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Published functional studies demonstrate a damaging effect (increase in stress granule abundance) (Hackman et al., 2013); This variant is associated with the following publications: (PMID: 23348830, 23401021, 10482271, 27282841, 28221306, 28817800, 30348846, 31321302, 33144682) -
Welander distal myopathy Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the TIA1 protein (p.Glu384Lys). This variant is present in population databases (rs747068278, gnomAD 0.007%). This missense change has been observed in individuals with Welander distal myopathy (WDM) (PMID: 10482271, 23348830, 23401021, 27282841). It is commonly reported in individuals of Finnish ancestry (PMID: 10482271, 23348830, 23401021, 27282841). ClinVar contains an entry for this variant (Variation ID: 41480). 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 tolerated. Experimental studies have shown that this missense change affects TIA1 function (PMID: 23401021, 28817800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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