19-6502208-C-T

Variant names:

• chr19-6502208-C-T
• rs587777467
• NM_006087.4:c.5G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_006087.4(TUBB4A):​c.5G>A​(p.Arg2Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.79

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6502209-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267773.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 19-6502208-C-T is Pathogenic according to our data. Variant chr19-6502208-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 139452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.5G>A	p.Arg2Gln	missense_variant	Exon 1 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.5G>A	p.Arg2Gln	missense_variant	Exon 1 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410414 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700424

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 29654

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 40790

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25040

Gnomad4 EAS exome AF: 0.0000280 AC: 1 AN: 35686

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 81832

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 39120

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1094758

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:4 Other:1

Jul 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23595291). 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TUBB4A protein function (PMID: 3405308). ClinVar contains an entry for this variant (Variation ID: 139452). This variant has been observed in individual(s) with clinical features of hypomyelinating leukodystrophy (PMID: 24785942, 24850488). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 2 of the TUBB4A protein (p.Arg2Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Sep 01, 2022

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 21, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 23, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBB4A c.5G>A (p.Arg2Gln) missense variant (also known as c.158G>A; p.Arg53Gln) has been reported in two studies in which it is identified in a heterozygous state in two individuals (Hamilton et al. 2014; Miyatake et al. 2014). Hamilton et al. (2014) identified the p.Arg2Gln variant in a presumed de novo state in a non-ambulatory 18 year-old female with nystagmus, intellectual disability, absent speech, g-tube dependent feeding, and abnormal MRI findings including an initially normal putamen and an almost complete lack of myelin. Miyatake et al. (2014) identified the p.Arg2Gln variant in a heterozygous state in a 15-year-old girl with severe intellectual disability, no head control, spasticity, rigidity, choreoathetosis, dystonia and MRI findings consistent with hypomyelinating leukodystrophy. Parental samples were not available for testing. Two additional patients with hypomyelination with atrophy of the basal ganglia and cerebellum with different missense variants at the same residue are also reported (Hamilton et al. 2014). The p.Arg2Gln variant was absent from 575 controls subjects (Miyatake et al. 2014) and is not found in the Genome Aggregation Database in a region of good sequence coverage. The p.Arg2Gln variant occurs within the MREI motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Hersheson et al. 2013). Based on the available evidence and the application of the ACMG criteria, the p.Arg2Gln variant is classified as pathogenic for TUBB4A-related leukodystrophy. -

not provided Pathogenic:1

Mar 23, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R2Q pathogenic variant in the TUBB4A gene has been reported multiple times previously in assocation with atrophy of the basal ganglia and cerebellum (H-ABC) (Miyatake et al., 2014; Hamilton et al., 2014). Additionally, missense variants in the same residue but involving different amino acid substitutions (R2W and R2G) have been reported in association with H-ABC and dystonia type 4 respectively (Hamilton et al., 2014; Hersheson et al., 2013). The R2Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a highly conserved position within the beta-tubulin tetrapeptide Met-Arg-Glu-Ile (MREI) motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Miyatake et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;T;.;.;.;T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	4.0	H;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.97	N;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift4G	Uncertain	0.022	D;D;.;.;D;D;.;D;.;.
Polyphen		0.94	P;.;.;.;.;.;.;.;.;.
Vest4		0.63
MutPred		0.48		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;
MVP		0.85
MPC		1.8
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.73
gMVP		0.82
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777467; hg19: chr19-6502219;