19-6495783-C-A

Variant names:

• chr19-6495783-C-A
• rs886041009
• NM_006087.4:c.716G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_006087.4(TUBB4A):​c.716G>T​(p.Cys239Phe) variant causes a missense change. 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.86
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_006087.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	NM_006087.4	MANE Select	c.716G>T	p.Cys239Phe	missense	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.869G>T	p.Cys290Phe	missense	Exon 5 of 5	NP_001276052.1
	TUBB4A	NM_001289127.2		c.851G>T	p.Cys284Phe	missense	Exon 5 of 5	NP_001276056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.716G>T	p.Cys239Phe	missense	Exon 4 of 4	ENSP00000264071.1
	TUBB4A	ENST00000598635.2	TSL:4	c.869G>T	p.Cys290Phe	missense	Exon 5 of 5	ENSP00000470627.2
	TUBB4A	ENST00000597686.6	TSL:4	c.851G>T	p.Cys284Phe	missense	Exon 5 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.83
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.70		Loss of catalytic residue at L240 (P = 0.1509)
MVP		0.79
MPC		3.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.94
gMVP		1.0
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: rs886041009; hg19: chr19-6495794;