rs886041013

Variant names:

• chr19-6495558-G-A
• rs886041013
• NM_006087.4:c.941C>T

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.941C>T​(p.Ala314Val) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB4A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. Gene score misZ: 4.2623 (above the threshold of 3.09). Trascript score misZ: 5.1229 (above the threshold of 3.09). GenCC associations: The gene is linked to torsion dystonia 4, TUBB4A-related neurologic disorder, hypomyelinating leukodystrophy 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 19-6495558-G-A is Pathogenic according to our data. Variant chr19-6495558-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.941C>T	p.Ala314Val	missense_variant	Exon 4 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.941C>T	p.Ala314Val	missense_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1
TUBB4A	ENST00000594075.5	c.*249C>T		downstream_gene_variant		3		ENSP00000469936.2
TUBB4A	ENST00000594276.5	c.*164C>T		downstream_gene_variant		4		ENSP00000472481.2
TUBB4A	ENST00000600216.5	c.*250C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:1 Other:1

Jun 17, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of TUBB4A-related conditions (PMID: 25545912, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 267783). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 314 of the TUBB4A protein (p.Ala314Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 04, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27809427, 25614026, 25545912) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.78
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.85
MutPred		0.38		Gain of sheet (P = 0.0827);
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.97

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: rs886041013; hg19: chr19-6495569;