rs761635539
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_006087.4(TUBB4A):c.568C>T(p.His190Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TUBB4A
NM_006087.4 missense
NM_006087.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 9.79
Genes affected
TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TUBB4A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
?
Variant 19-6495931-G-A is Pathogenic according to our data. Variant chr19-6495931-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192383.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB4A | NM_006087.4 | c.568C>T | p.His190Tyr | missense_variant | 4/4 | ENST00000264071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB4A | ENST00000264071.7 | c.568C>T | p.His190Tyr | missense_variant | 4/4 | 1 | NM_006087.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251492Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 6 Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TUBB4A protein function. ClinVar contains an entry for this variant (Variation ID: 192383). This missense change has been observed in individual(s) with TUBB4A-related conditions (PMID: 25772097, 27538619). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 190 of the TUBB4A protein (p.His190Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.
REVEL
Pathogenic
Sift4G
Uncertain
D;D;.;.
Polyphen
D;.;.;.
Vest4
MutPred
Loss of catalytic residue at L192 (P = 0.1625);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at