rs1555754019

chr19-6495730-T-Achr19-6495730-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M257V) has been classified 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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_006087.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUBB4A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.769A>T	p.Met257Leu	missense_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.769A>T	p.Met257Leu	missense_variant	4/4	1	NM_006087.4	P1
TUBB4A	ENST00000594276.5	c.457A>T	p.Met153Leu	missense_variant	3/3	4

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2017

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. 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. 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"). 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). -

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;.
MutationTaster	Benign	1.0	D;D
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;