rs587776983

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_006087.4(TUBB4A):​c.4C>T​(p.Arg2Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TUBB4A
NM_006087.4 missense

Scores

9
7
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 1.53
Variant links:
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]

Genome browser will be placed here

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 in gene, where missense usually causes diseases (based on misZ statistic), TUBB4A. . Gene score misZ 4.2623 (greater than the threshold 3.09). Trascript score misZ 5.1229 (greater than threshold 3.09). GenCC has associacion of gene with torsion dystonia 4, TUBB4A-related neurologic disorder, hypomyelinating leukodystrophy 6.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865
PP5
Variant 19-6502209-G-A is Pathogenic according to our data. Variant chr19-6502209-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267773.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TUBB4ANM_006087.4 linkuse as main transcriptc.4C>T p.Arg2Trp missense_variant 1/4 ENST00000264071.7 NP_006078.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TUBB4AENST00000264071.7 linkuse as main transcriptc.4C>T p.Arg2Trp missense_variant 1/41 NM_006087.4 ENSP00000264071 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1407616
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
698750
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 14, 2019- -
Hypomyelinating leukodystrophy 6 Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;.;.;T;.;.;.;T;T;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
1.0
D;D;D;D;T;D;D;D;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Pathogenic
4.6
H;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-2.1
N;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.87
Sift4G
Pathogenic
0.0
D;D;.;.;D;D;.;D;.;.
Polyphen
1.0
D;.;.;.;.;.;.;.;.;.
Vest4
0.72
MutPred
0.55
Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);.;Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);.;
MVP
0.88
MPC
2.4
ClinPred
1.0
D
GERP RS
3.2
Varity_R
0.68
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776983; hg19: chr19-6502220; API