rs886041015

Variant names:

• chr19-6495445-C-A
• rs886041015
• NM_006087.4:c.1054G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6495445-C-A
• chr19-6495445-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_006087.4(TUBB4A):​c.1054G>T​(p.Ala352Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.76

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB4A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. Gene score misZ: 4.2623 (above the threshold of 3.09). Trascript score misZ: 5.1229 (above the threshold of 3.09). GenCC associations: The gene is linked to torsion dystonia 4, TUBB4A-related neurologic disorder, hypomyelinating leukodystrophy 6.
• PP5: Variant 19-6495445-C-A is Pathogenic according to our data. Variant chr19-6495445-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 807519.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.1054G>T	p.Ala352Ser	missense_variant	Exon 4 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.1054G>T	p.Ala352Ser	missense_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Pathogenic:1

May 07, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.016
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.45	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.43
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.63
MutPred		0.31		Loss of sheet (P = 0.0817);
MVP		0.64
MPC		2.6
ClinPred		0.94	D
GERP RS		3.4
Varity_R		0.78
gMVP		0.95

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

Other links and lift over

dbSNP: rs886041015; hg19: chr19-6495456;