6-30722640-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_178014.4(TUBB):​c.161C>T​(p.Ala54Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

TUBB
NM_178014.4 missense

Scores

3
7
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.77
Variant links:
Genes affected
TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB. . Gene score misZ: 5.6252 (greater than the threshold 3.09). Trascript score misZ: 8.3435 (greater than threshold 3.09). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the gene with multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, TUBB3-related tubulinopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TUBBNM_178014.4 linkc.161C>T p.Ala54Val missense_variant 2/4 ENST00000327892.13 NP_821133.1 P07437Q5SU16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TUBBENST00000327892.13 linkc.161C>T p.Ala54Val missense_variant 2/41 NM_178014.4 ENSP00000339001.7 P07437

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple benign circumferential skin creases on limbs 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingPittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical CenterNov 22, 2023This sequence variant is a single nucleotide substitution (C>T) at position 161 of the coding sequence of the TUBB gene that results in an alanine to valine amino acid change at residue 54 of the tubulin beta class I protein. This is a previously reported variant (ClinVar 1031753) that has not been observed in the literature in individuals affected by TUBB-related disease, to our knowledge. This variant is absent from the gnomAD population database (0/~152000 alleles). Multiple bioinformatic tools predict that this alanine to valine amino acid change would be neutral, and the Ala54 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4, PM2 -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 28, 2018This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Complex cortical dysplasia with other brain malformations 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 24, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however dominant negative and loss of function have been suggested (PMIDs: 23246003, 26637975). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by a clinical laboratory in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.054
T;T
Eigen
Benign
0.090
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.090
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.0
M;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.7
N;N
REVEL
Uncertain
0.53
Sift4G
Benign
0.18
T;T
Polyphen
0.011
B;.
Vest4
0.80
MutPred
0.59
Loss of catalytic residue at A54 (P = 0.0706);.;
MVP
0.97
MPC
1.8
ClinPred
0.98
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.72
gMVP
0.92

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1776362492; hg19: chr6-30690417; API