Genetic Variant TUBB4A:p.Arg2Pro (chr19-6502208-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_006087.4(TUBB4A):c.5G>C(p.Arg2Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 7.1e-7 ( 0 hom. )

Consequence

TUBB4A
NM_006087.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.79

Publications

11 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, 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

TUBB4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4 link	c.5G>C	p.Arg2Pro	missense_variant	Exon 1 of 4	ENST00000264071.7	NP_006078.2	P04350

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7 link	c.5G>C	p.Arg2Pro	missense_variant	Exon 1 of 4	1	NM_006087.4	ENSP00000264071.1		P04350

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000565

AC:

AN:

176952

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29654

American (AMR)

AF:

0.00

AC:

AN:

40790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25040

East Asian (EAS)

AF:

0.00

AC:

AN:

35686

South Asian (SAS)

AF:

0.00

AC:

AN:

81832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5002

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094758

Other (OTH)

AF:

0.00

AC:

AN:

58532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.18

T;.;.;T;.;.;.;T;T;.

Eigen

Benign

0.086

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D;T;T;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;.;.;.;.;.

PhyloP100

5.8

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

N;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.61

Sift4G

Uncertain

0.0070

D;D;.;.;D;D;.;D;.;.

Polyphen

0.021

B;.;.;.;.;.;.;.;.;.

Vest4

0.77

MutPred

0.51

Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);.;Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);.;

MVP

0.79

MPC

2.0

ClinPred

0.97

GERP RS

2.1

PromoterAI

0.26

Neutral

(source)

Varity_R

0.88

gMVP

0.97

Mutation Taster

=65/35

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over