19-6502208-C-T

Variant names:

• chr19-6502208-C-T
• rs587777467
• NM_006087.4:c.5G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001289123.2(TUBB4A):​c.158G>A​(p.Arg53Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R53G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TUBB4A NM_001289123.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.79
• 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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6502209-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 50984.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 19-6502208-C-T is Pathogenic according to our data. Variant chr19-6502208-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 139452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289123.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	NM_006087.4	MANE Select	c.5G>A	p.Arg2Gln	missense	Exon 1 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.158G>A	p.Arg53Gln	missense	Exon 2 of 5	NP_001276052.1
	TUBB4A	NM_001289127.2		c.140G>A	p.Arg47Gln	missense	Exon 2 of 5	NP_001276056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.5G>A	p.Arg2Gln	missense	Exon 1 of 4	ENSP00000264071.1
	TUBB4A	ENST00000598635.2	TSL:4	c.158G>A	p.Arg53Gln	missense	Exon 2 of 5	ENSP00000470627.2
	TUBB4A	ENST00000597686.6	TSL:4	c.140G>A	p.Arg47Gln	missense	Exon 2 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410414 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29654

American (AMR) AF: 0.00 AC: 0 AN: 40790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25040

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35686

South Asian (SAS) AF: 0.00 AC: 0 AN: 81832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5002

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094758

Other (OTH) AF: 0.00 AC: 0 AN: 58532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypomyelinating leukodystrophy 6 (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.97	N
REVEL	Pathogenic	0.80
Sift4G	Uncertain	0.022	D
Polyphen		0.94	P
Vest4		0.63
MutPred		0.48		Loss of sheet (P = 0.1158)
MVP		0.85
MPC		1.8
ClinPred		1.0	D
GERP RS		2.1
PromoterAI		0.059	Neutral
Varity_R		0.73
gMVP		0.82
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777467; hg19: chr19-6502219;