rs483352809

Variant names:

• chr19-6495754-C-T
• rs483352809
• NM_006087.4:c.745G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_006087.4(TUBB4A):​c.745G>A​(p.Asp249Asn) 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:14 O:2
• Conservation: PhyloP100: 7.70
• Publications: 35 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_006087.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 19-6495754-C-T is Pathogenic according to our data. Variant chr19-6495754-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50985.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.745G>A	p.Asp249Asn	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.745G>A	p.Asp249Asn	missense_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:8 Other:2

Jan 01, 2023

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 21, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050985). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23582646, 24706558, 25545912). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the TUBB4A protein (p.Asp249Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID: 23582646, 24706558, 25545912). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50985). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TUBB4A protein function. Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). For these reasons, this variant has been classified as Pathogenic. -

Jan 25, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3, PM1, PM2_SUP, PP3 -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 13-year-old male with a progressive neurological disorder with mild intellectual disability, hypotonia at 17m (resolved), ataxia, spasticity, dystonia, possible seizures, short stature, microcephaly, hyperopia, brain abnormalities. -

Oct 29, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBB4A c.745G>A missense variant is classified as PATHOGENIC (PS4_moderate, PM2, PS2, PP2, PP3) The TUBB4A c.745G>A missense variant is a single nucleotide change in exon 4 of the TUBB4A gene, which is predicted to change the amino acid aspartic acid at position 249 in the protein to asparagine. This recurrent variant has been reported in multiple patients with leukodystrophy, specifically, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID:23582646, PMID:24785942) (PS4_moderate). This variant is de novo in this patient and in the majority of reported cases in the literature (PS2). The variant is in dbSNP (rs483352809) but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (Variation ID:50985). The variant is a missense variant in a gene with low rate of benign missense variants (PP2). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

-

Texas Scottish Rite Hospital for Children

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 30, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.745G>A, p.Asp248Asn) has not been observed in population databases (gnomAD), but the change has been reported in the literature (PMID 24785942, PMID 23582646, PMID 16707859, PMID 7983175, PMID 24850488, PMID 18466252, PMID 30079973, PMID 28973395). Variant prediction programs suggest a deleterious effect, and this is supported in published functional studies (PMID 30079973, PMID 28973395). It has been seen in 3 unrelated affected individuals in this laboratory. -

not provided Pathogenic:4

May 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34514881, 23582646, 28973395, 30079973, 30350845, 32371413, 32463361, 7983175, 25326635, 24785942, 24706558, 24850488, 25545912, 32005694, 35586607) -

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the nervous system Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Torsion dystonia 4;C2676244:Hypomyelinating leukodystrophy 6 Pathogenic:1

Jan 15, 2019

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PS2, PS3, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;.
REVEL	Pathogenic	0.84
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.76		Loss of ubiquitination at K252 (P = 0.0488);.;
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.98
Mutation Taster		=6/94	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: rs483352809; hg19: chr19-6495765;