rs121918555
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PP3_StrongPP5_Very_StrongBS2_Supporting
The NM_030773.4(TUBB1):c.952C>T(p.Arg318Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,146 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_030773.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB1 | NM_030773.4 | c.952C>T | p.Arg318Trp | missense_variant | 4/4 | ENST00000217133.2 | |
TUBB1 | XM_017028085.2 | c.886C>T | p.Arg296Trp | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB1 | ENST00000217133.2 | c.952C>T | p.Arg318Trp | missense_variant | 4/4 | 1 | NM_030773.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251326Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135858
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461834Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 727212
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74482
ClinVar
Submissions by phenotype
Macrothrombocytopenia, isolated, 1, autosomal dominant Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2009 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 09, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 07, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 318 of the TUBB1 protein (p.Arg318Trp). This variant is present in population databases (rs121918555, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TUBB1-related macrothrombocytopenia (PMID: 18849486, 31064749, 33400601). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 425). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects TUBB1 function (PMID: 18849486). For these reasons, this variant has been classified as Pathogenic. - |
Macrothrombocytopenia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at