rs797045074

Positions:

• chr19-6495335-C-G
• chr19-6495335-C-T

Variant summary

Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006087.4(TUBB4A):​c.1164G>C​(p.Met388Ile) 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M388T) has been classified 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
• Conservation: PhyloP100: 7.77

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 27 ACMG points.

• PS1: Transcript NM_006087.4 (TUBB4A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 267792
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006087.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6495337-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.949
• PP5: Variant 19-6495335-C-G is Pathogenic according to our data. Variant chr19-6495335-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.1164G>C	p.Met388Ile	missense_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.1164G>C	p.Met388Ile	missense_variant	4/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB4A protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209201). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy (PMID: 24785942, 32581362, 33597727). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 388 of the TUBB4A protein (p.Met388Ile). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 05, 2014	Likely pathogenicity based on finding it once in our laboratory de novo in a 22-year-old female with spastic paraplegia, epilepsy, hyperreflexia, absent speech, severe cognitive delays, severe scoliosis, leukodystrophy, ventriculomegaly, microcephaly, osteoporosis, hip dislocation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.99
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.80		Loss of MoRF binding (P = 0.0887);
MVP		0.91
MPC		1.6
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.92
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: rs797045074; hg19: chr19-6495346;