2-70212810-T-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_022173.4(TIA1):c.1070A>G(p.Asn357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,613,982 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_022173.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00582 AC: 886AN: 152144Hom.: 6 Cov.: 32
GnomAD3 exomes AF: 0.00665 AC: 1673AN: 251424Hom.: 17 AF XY: 0.00696 AC XY: 946AN XY: 135884
GnomAD4 exome AF: 0.00737 AC: 10773AN: 1461720Hom.: 70 Cov.: 30 AF XY: 0.00758 AC XY: 5515AN XY: 727170
GnomAD4 genome AF: 0.00582 AC: 886AN: 152262Hom.: 6 Cov.: 32 AF XY: 0.00544 AC XY: 405AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
TIA1: BP4, BS2 -
BP4 -
This variant is associated with the following publications: (PMID: 29886022, 29599744, 26627873, 29457785) -
TIA1-related disorder Pathogenic:1
The TIA1 c.1070A>G variant is predicted to result in the amino acid substitution p.Asn357Ser. This variant has been reported in the heterozygous state in at least 15 individuals to cause a digenically inherited distal myopathy when in the presence of a pathogenic SQSTM1 variant (Evilä et al. 2016. PubMed ID: 26627873; Niu et al. 2018. PubMed ID: 29599744; Lee et al. 2018. PubMed ID: 29457785). Functional studies have shown that the c.1070A>G variant dictates a myodegenerative phenotype by disrupting stress granule homeostasis and ubiquitin-mediated autophagic degradation (Lee et al. 2018. PubMed ID: 29457785). Therefore, the c.1070A>G variant (whether heterozygous or homozygous) is only pathogenic for a myopathy phenotype when co-inherited with a pathogenic SQSTM1 variant. -
Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia Uncertain:1
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not specified Benign:1
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Welander distal myopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at