rs587777467

chr19-6502208-C-Gchr19-6502208-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_006087.4(TUBB4A):c.5G>C(p.Arg2Pro) 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. R2G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TUBB4A NM_006087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-6502208-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 139452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBB4A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.5G>C	p.Arg2Pro	missense_variant	1/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.5G>C	p.Arg2Pro	missense_variant	1/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000565 AC: 1 AN: 176952 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 98698

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;.;T;.;.;.;T;T;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;T;T;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift4G	Uncertain	0.0070	D;D;.;.;D;D;.;D;.;.
Polyphen		0.021	B;.;.;.;.;.;.;.;.;.
Vest4		0.77
MutPred		0.51		Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);.;Gain of catalytic residue at R2 (P = 0.0084);Gain of catalytic residue at R2 (P = 0.0084);.;
MVP		0.79
MPC		2.0
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.88
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777467; hg19: chr19-6502219;