rs797046074

Variant names:

• chr6-3154168-T-A
• rs797046074
• NM_001069.3:c.1033A>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_001069.3(TUBB2A):​c.1033A>T​(p.Ile345Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: TUBB2A NM_001069.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.75

Genes affected

TUBB2A (HGNC:12412): (tubulin beta 2A class IIa) Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PP2: Missense variant in the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 5, tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 6-3154168-T-A is Pathogenic according to our data. Variant chr6-3154168-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB2A	NM_001069.3	c.1033A>T	p.Ile345Phe	missense_variant	Exon 4 of 4	ENST00000333628.4	NP_001060.1
TUBB2A	NM_001310315.2	c.778A>T	p.Ile260Phe	missense_variant	Exon 4 of 4		NP_001297244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB2A	ENST00000333628.4	c.1033A>T	p.Ile345Phe	missense_variant	Exon 4 of 4	1	NM_001069.3	ENSP00000369703.2

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 11

GnomAD4 genome Cov.: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 5 Pathogenic:2

Apr 24, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TUBB2A-related tubulinopathy Pathogenic:1

Dec 09, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBB2A c.1033A>T (p.Ile345Phe) variant is a missense variant that has been identified in a de novo heterozygous state in an individual with developmental delay, epilepsy, seizures, infantile spasms, perisylvian polymicrogyria, microcephaly and plagiocephaly (Lee et al. 2014). The p.Ile345Phe variant is not found in the Genome Aggregation Database in a region of reasonably good sequence coverage, suggesting that it is a rare variant. Additionally, it is located in a C-terminal domain of the TUBB2A gene that is important for protein interaction (Cai et al. 2020) and in silico tools predict damaging effect of the variant on the protein. Based on the collective evidence and application of the ACMG criteria, the p.Ile345Phe variant is classified as pathogenic for TUBB2A-related tubulinopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.75		Loss of ubiquitination at K350 (P = 0.1498);
MVP		0.95
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.76
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs797046074; hg19: chr6-3154402;