rs587777468

Positions:

• chr19-6495966-G-A
• chr19-6495966-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006087.4(TUBB4A):​c.533C>T​(p.Thr178Met) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.80

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]

TUBB4A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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, 0.904
• PP5: Variant 19-6495966-G-A is Pathogenic according to our data. Variant chr19-6495966-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.533C>T	p.Thr178Met	missense_variant	4/4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.533C>T	p.Thr178Met	missense_variant	4/4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	May 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	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, 33027950, 36187477, 34997144, 34120799, 34869359, 36939041, 26643067, 34514881, 35936629, 35661708) -

Torsion dystonia 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 26643067] -

Hypomyelinating leukodystrophy 6 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.4	H;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D;.;.;.
REVEL	Pathogenic	0.81
Sift4G	Uncertain	0.019	D;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.85
MutPred		0.63		Loss of ubiquitination at K174 (P = 0.0609);.;.;.;
MVP		0.84
MPC		2.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs587777468; hg19: chr19-6495977;