12-49185218-G-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_006009.4(TUBA1A):c.1148C>A(p.Ala383Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A383V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006009.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBA1A | NM_006009.4 | c.1148C>A | p.Ala383Asp | missense_variant | 4/4 | ENST00000301071.12 | |
TUBA1A | NM_001270399.2 | c.1148C>A | p.Ala383Asp | missense_variant | 4/4 | ||
TUBA1A | NM_001270400.2 | c.1043C>A | p.Ala348Asp | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBA1A | ENST00000301071.12 | c.1148C>A | p.Ala383Asp | missense_variant | 4/4 | 1 | NM_006009.4 | P1 | |
TUBA1B-AS1 | ENST00000656133.1 | n.474-3065G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2017 | The A383D variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A383D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position and missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with TUBA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, GeneDx interprets A383D as a variant, likely pathogenic - |
Tubulinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | literature only | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Jul 01, 2018 | A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.1148C>A, p.(Ala383Asp) variant has been reported as a variant of germline/unknown origin. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at