rs587776983

chr19-6502209-G-Achr19-6502209-G-Cchr19-6502209-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006087.4(TUBB4A):c.4C>T(p.Arg2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6502208-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 139452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBB4A
• 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 id is 267773.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.4C>T	p.Arg2Trp	missense_variant	1/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.4C>T	p.Arg2Trp	missense_variant	1/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407616 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 14, 2019

- -

Hypomyelinating leukodystrophy 6 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;T;.;.;.;T;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.87
Sift4G	Pathogenic	0.0	D;D;.;.;D;D;.;D;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.55		Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);.;Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);.;
MVP		0.88
MPC		2.4
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.68
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs587776983; hg19: chr19-6502220;