rs1555754019

Variant names:

• chr19-6495730-T-A
• rs1555754019
• NM_006087.4:c.769A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6495730-T-A
• chr19-6495730-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006087.4(TUBB4A):​c.769A>T​(p.Met257Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.769A>T	p.Met257Leu	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.769A>T	p.Met257Leu	missense_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Uncertain:1

Nov 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with TUBB4A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 257 of the TUBB4A protein (p.Met257Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.89	N;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.45
Sift4G	Benign	0.53	T;T
Polyphen		0.0	B;.
Vest4		0.72
MutPred		0.39		Gain of methylation at R262 (P = 0.1188);.;
MVP		0.60
MPC		2.6
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.91
gMVP		0.99

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: rs1555754019; hg19: chr19-6495741;