19-6502208-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001289123.2(TUBB4A):​c.158G>C​(p.Arg53Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 5 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, 0.758

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>C	p.Arg2Pro	missense	Exon 1 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.158G>C	p.Arg53Pro	missense	Exon 2 of 5	NP_001276052.1
	TUBB4A	NM_001289127.2		c.140G>C	p.Arg47Pro	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>C	p.Arg2Pro	missense	Exon 1 of 4	ENSP00000264071.1
	TUBB4A	ENST00000598635.2	TSL:4	c.158G>C	p.Arg53Pro	missense	Exon 2 of 5	ENSP00000470627.2
	TUBB4A	ENST00000597686.6	TSL:4	c.140G>C	p.Arg47Pro	missense	Exon 2 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000565 AC: 1 AN: 176952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410414 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700424

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: 0.00 AC: 0 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: 9.13e-7 AC: 1 AN: 1094758

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.086
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.61
Sift4G	Uncertain	0.0070	D
Polyphen		0.021	B
Vest4		0.77
MutPred		0.51		Gain of catalytic residue at R2 (P = 0.0084)
MVP		0.79
MPC		2.0
ClinPred		0.97	D
GERP RS		2.1
PromoterAI		0.26	Neutral
Varity_R		0.88
gMVP		0.97
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs587777467; hg19: chr19-6502219;