rs587777429

Positions:

• chr19-6496032-C-A
• chr19-6496032-C-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.467G>T​(p.Arg156Leu) 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:4 O:1
• Conservation: PhyloP100: 7.78

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 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, 0.916
• PP5: Variant 19-6496032-C-A is Pathogenic according to our data. Variant chr19-6496032-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6496032-C-A is described in Lovd as [Pathogenic]. Variant chr19-6496032-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.467G>T	p.Arg156Leu	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.467G>T	p.Arg156Leu	missense_variant	4/4	1	NM_006087.4	ENSP00000264071	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 17, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects TUBB4A protein function (PMID: 28275661). This variant has been observed in individual(s) with TUBB4A-related conditions (PMID: 24742798, 26795593). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 135659). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 156 of the TUBB4A protein (p.Arg156Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2014

The c.467G>T (p.R156L) alteration is located in exon 4 (coding exon 4) of the TUBB4A gene. This alteration results from a G to T substitution at nucleotide position 467, causing the arginine (R) at amino acid position 156 to be replaced by a leucine (L). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the TUBB4A c.467G>T alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP)._x000D_ Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ This missense alteration was reported in de novo form in a 4-year old Caucasian girl tested at Ambry Genetics through exome sequencing with static hypomyelinating leukodystrophy (Purnell, 2014). Her features included hypotonia, global delay, truncal ataxia, nystagmus, esotropia, and hypomyelination on brain MRI with minor atrophy of the brain stem and cerebellum. The altered amino acid is conserved throughout evolution:_x000D_ The p.R156 amino acid is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.R156L amino acid is located within the H4 a-helix of the globular N-terminal nucleotide binding domain of the tubulin b-4A protein (Lowe, 2001). The alteration is predicted deleterious by in silico models:_x000D_ The p.R156L alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

TUBB4A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The TUBB4A c.467G>T variant is predicted to result in the amino acid substitution p.Arg156Leu. This variant has been reported as de novo in an individual with hypotonia, nystagmus, and hypomyelination (Purnell et al. 2014. PubMed ID: 24742798), de novo in an individual with unclassified epilepsy (Table S3, Helbig et al 2016. PubMed ID: 26795593), and with unknown inheritance in two individuals with hypomyelination (Table S1, Gavazzi et al. 2021. PubMed ID: 34514881). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.3	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D;.;.
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.66		Loss of disorder (P = 0.0948);.;.;
MVP		0.81
MPC		1.9
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
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: rs587777429; hg19: chr19-6496043;