rs886041021

Variant names:

• chr19-6495327-C-A
• rs886041021
• NM_006087.4:c.1172G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6495327-C-A
• chr19-6495327-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_006087.4(TUBB4A):​c.1172G>T​(p.Arg391Leu) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.77
• Publications: 11 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006087.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6495327-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 267793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 19-6495327-C-A is Pathogenic according to our data. Variant chr19-6495327-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419697.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.1172G>T	p.Arg391Leu	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.1172G>T	p.Arg391Leu	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Apr 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25085639, 34514881, 35599849) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypomyelinating leukodystrophy 6 Pathogenic:1 Uncertain:1

Feb 23, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 391 of the TUBB4A protein (p.Arg391Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TUBB4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 419697). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg391 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25085639; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.95
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.84		Loss of MoRF binding (P = 0.0345);
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.86
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041021; hg19: chr19-6495338;