rs886041021

Positions:

• chr19-6495327-C-A
• chr19-6495327-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_006087.4(TUBB4A):​c.1172G>T​(p.Arg391Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr19-6495327-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 267793.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, 0.972
• PP5: Variant 19-6495327-C-A is Pathogenic according to our data. Variant chr19-6495327-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419697.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.1172G>T	p.Arg391Leu	missense_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.1172G>T	p.Arg391Leu	missense_variant	4/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2022	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. This variant disrupts the p.Arg391 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25085639; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 419697). This variant has not been reported in the literature in individuals affected with TUBB4A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 391 of the TUBB4A protein (p.Arg391Leu). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2015

The R391L variant in the TUBB4A gene has not been reported previously as a pathogenic variantnor as a benign polymorphism, to our knowledge. The R391L substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R391L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (M388V, M388T, M388I, and F394C) have been reported in the Human Gene Mutation Database in association with hypomyelination with atrophy of the basal ganglia and cerebellum (Stenson et al., 2014), supporting the functional importance of this region of the protein. A different amino acid change at the same location (R391H) has been reported in an individual with isolated hypomyelination (Pizzano et al., 2014). We interpret R391L as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.95
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.84		Loss of MoRF binding (P = 0.0345);
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.86
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: rs886041021; hg19: chr19-6495338;