Variant 19-6495769-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_006087.4(TUBB4A):c.730G>C(p.Gly244Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TUBB4A
NM_006087.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.70

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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, 0.969

PP5

Variant 19-6495769-C-G is Pathogenic according to our data. Variant chr19-6495769-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 803516.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4 linkuse as main transcript	c.730G>C	p.Gly244Arg	missense_variant	4/4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TUBB4A	ENST00000264071.7 linkuse as main transcript	c.730G>C	p.Gly244Arg	missense_variant	4/4	1	NM_006087.4	ENSP00000264071	P1
TUBB4A	ENST00000594276.5 linkuse as main transcript	c.418G>C	p.Gly140Arg	missense_variant	3/3	4		ENSP00000472481
TUBB4A	ENST00000594075.5 linkuse as main transcript			downstream_gene_variant		3		ENSP00000469936
TUBB4A	ENST00000600216.5 linkuse as main transcript			downstream_gene_variant		5		ENSP00000470983

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.0

D;.

REVEL

Pathogenic

0.96

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.82

Gain of MoRF binding (P = 0.02);.;

MVP

0.88

MPC

3.0

ClinPred

1.0

GERP RS

4.0

Varity_R

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over