Genetic Variant TUBB4A:p.Arg2Trp (chr19-6502209-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_006087.4(TUBB4A):c.4C>T(p.Arg2Trp) variant causes a missense change involving the alteration of a non-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 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBB4A
NM_006087.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 1.53

Publications

35 publications found

Variant links:

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, Orphanet, Labcorp Genetics (formerly Invitae), 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

TUBB4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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-C is described in ClinVar as Pathogenic. ClinVar VariationId is 50984.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 19-6502209-G-A is Pathogenic according to our data. Variant chr19-6502209-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 267773.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBB4A	NM_006087.4	MANE Select	c.4C>T	p.Arg2Trp	missense	Exon 1 of 4	NP_006078.2
TUBB4A	NM_001289123.2		c.157C>T	p.Arg53Trp	missense	Exon 2 of 5	NP_001276052.1	M0QZL7
TUBB4A	NM_001289127.2		c.139C>T	p.Arg47Trp	missense	Exon 2 of 5	NP_001276056.1	M0R278

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.4C>T	p.Arg2Trp	missense	Exon 1 of 4	ENSP00000264071.1	P04350
TUBB4A	ENST00000598635.2	TSL:4	c.157C>T	p.Arg53Trp	missense	Exon 2 of 5	ENSP00000470627.2	M0QZL7
TUBB4A	ENST00000597686.6	TSL:4	c.139C>T	p.Arg47Trp	missense	Exon 2 of 5	ENSP00000472375.2	M0R278

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1407616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698750

African (AFR)

AF:

0.00

AC:

AN:

29552

American (AMR)

AF:

0.00

AC:

AN:

40358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.00

AC:

AN:

35480

South Asian (SAS)

AF:

0.00

AC:

AN:

81582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4954

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093332

Other (OTH)

AF:

0.00

AC:

AN:

58426

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Hypomyelinating leukodystrophy 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

4.6

PhyloP100

1.5

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.87

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.72

MutPred

0.55

Loss of disorder (P = 0.0172)

MVP

0.88

MPC

2.4

ClinPred

1.0

GERP RS

3.2

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.68

gMVP

0.88

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over