chr19-6495769-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_006087.4(TUBB4A):c.730G>A(p.Gly244Ser) 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. G244D) has been classified as Uncertain significance.
Frequency
Consequence
NM_006087.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB4A | NM_006087.4 | c.730G>A | p.Gly244Ser | missense_variant | 4/4 | ENST00000264071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB4A | ENST00000264071.7 | c.730G>A | p.Gly244Ser | missense_variant | 4/4 | 1 | NM_006087.4 | P1 | |
TUBB4A | ENST00000594276.5 | c.418G>A | p.Gly140Ser | missense_variant | 3/3 | 4 | |||
TUBB4A | ENST00000594075.5 | downstream_gene_variant | 3 | ||||||
TUBB4A | ENST00000600216.5 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypomyelinating leukodystrophy 6 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2023 | Variant summary: TUBB4A c.730G>A (p.Gly244Ser) results in a non-conservative amino acid change located in the GTPase domain (IPR003008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.730G>A has been reported in the literature in at least five individuals affected with Hypomyelinating Leukodystrophy, including several de novo occurrences (e.g., Hamilton_2014, Carvalho_2015, Gavazzi_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34514881, 24785942, 25168210). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27809427, 24785942, 33027950, 25168210, 34514881) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at