chr19-6495966-G-C

Variant names:

• chr19-6495966-G-C
• rs587777468
• NM_006087.4:c.533C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_006087.4(TUBB4A):​c.533C>G​(p.Thr178Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T178M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.80
• Publications: 9 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 10 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr19-6495966-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 267774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 19-6495966-G-C is Pathogenic according to our data. Variant chr19-6495966-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 139453.Status of the report is criteria_provided_single_submitter, 1 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.533C>G	p.Thr178Arg	missense	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.686C>G	p.Thr229Arg	missense	Exon 5 of 5	NP_001276052.1
	TUBB4A	NM_001289127.2		c.668C>G	p.Thr223Arg	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.533C>G	p.Thr178Arg	missense	Exon 4 of 4	ENSP00000264071.1
	TUBB4A	ENST00000598635.2	TSL:4	c.686C>G	p.Thr229Arg	missense	Exon 5 of 5	ENSP00000470627.2
	TUBB4A	ENST00000597686.6	TSL:4	c.668C>G	p.Thr223Arg	missense	Exon 5 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:2 Other:1

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

Dec 29, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.533C>G, p.Thr178Arg) has not been observed in population databases (gnomAD). It has been reported in the literature (PMID 24850488, PMID 30476126). Variant prediction programs suggest a deleterious effect, although no functional studies have been published.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.63		Loss of phosphorylation at T178 (P = 0.0853)
MVP		0.84
MPC		2.9
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.98
Mutation Taster		=4/96	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: rs587777468; hg19: chr19-6495977;