rs886041014

Variant names:

• chr19-6495531-A-C
• rs886041014
• NM_006087.4:c.968T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006087.4(TUBB4A):​c.968T>G​(p.Met323Arg) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.06
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Illumina
• TUBB4A-related neurologic disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• torsion dystonia 4

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.968T>G	p.Met323Arg	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.968T>G	p.Met323Arg	missense_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Uncertain:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 11, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with TUBB4A-related disorder (PMID: 24785942). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D
Sift4G	Uncertain	0.046	D
Vest4		0.90
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.98
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041014; hg19: chr19-6495542;