rs483352809

Positions:

• chr19-6495754-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.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

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, 0.93
• PP5: Variant 19-6495754-C-T is Pathogenic according to our data. Variant chr19-6495754-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495754-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.745G>A	p.Asp249Asn	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.745G>A	p.Asp249Asn	missense_variant	4/4	1	NM_006087.4	ENSP00000264071.1
TUBB4A	ENST00000594276.5	c.433G>A	p.Asp145Asn	missense_variant	3/3	4		ENSP00000472481.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 25, 2022	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3, PM1, PM2_SUP, PP3 -
not provided, no classification provided	literature only	Texas Scottish Rite Hospital for Children	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 29, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 30, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 50985). 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. This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 15, 2019

[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;.
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

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: rs483352809; hg19: chr19-6495765;