19-6495335-C-T

Variant names:

• chr19-6495335-C-T
• rs797045074
• NM_006087.4:c.1164G>A

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006087.4(TUBB4A):​c.1164G>A​(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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in 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 criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.77
• Publications: 7 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 26 ACMG points.

• PS1: Transcript NM_006087.4 (TUBB4A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 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 chr19-6495336-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 267791.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 19-6495335-C-T is Pathogenic according to our data. Variant chr19-6495335-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 267792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	NM_006087.4	MANE Select	c.1164G>A	p.Met388Ile	missense	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.1317G>A	p.Met439Ile	missense	Exon 5 of 5	NP_001276052.1
	TUBB4A	NM_001289127.2		c.1299G>A	p.Met433Ile	missense	Exon 5 of 5	NP_001276056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.1164G>A	p.Met388Ile	missense	Exon 4 of 4	ENSP00000264071.1
	TUBB4A	ENST00000598635.2	TSL:4	c.1317G>A	p.Met439Ile	missense	Exon 5 of 5	ENSP00000470627.2
	TUBB4A	ENST00000597686.6	TSL:4	c.1299G>A	p.Met433Ile	missense	Exon 5 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:1 Other:1

May 29, 2023

Genetics and Molecular Pathology, SA Pathology

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

Global developmental delay;C2677328:Cerebral hypomyelination;C3279222:Aplasia/Hypoplasia of the cerebellum;C4022595:Tetraplegia/tetraparesis;C4022745:Abnormal basal ganglia MRI signal intensity;C4551563:Microcephaly Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:1

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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	0.94	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
PhyloP100		7.8
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
Mutation Taster		=26/74	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: rs797045074; hg19: chr19-6495346;