rs587777355
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_178014.4(TUBB):c.895A>G(p.Met299Val) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M299I) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TUBB
NM_178014.4 missense
NM_178014.4 missense
Scores
7
9
1
Clinical Significance
Conservation
PhyloP100: 7.12
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 Pathogenic. Variant got 17 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr6-30723959-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338518.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, TUBB
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
?
Variant 6-30723957-A-G is Pathogenic according to our data. Variant chr6-30723957-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 127189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null. Variant chr6-30723957-A-G is described in UniProt as null.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB | NM_178014.4 | c.895A>G | p.Met299Val | missense_variant | 4/4 | ENST00000327892.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB | ENST00000327892.13 | c.895A>G | p.Met299Val | missense_variant | 4/4 | 1 | NM_178014.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Complex cortical dysplasia with other brain malformations 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 04, 2024 | Criteria applied: PS2,PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 27, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.895A>G (p.M299V) alteration is located in exon 4 (coding exon 4) of the TUBB gene. This alteration results from an A to G substitution at nucleotide position 895, causing the methionine (M) at amino acid position 299 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported as a de novo occurrence in an individual with microcephaly, brain anomalies, developmental delay, ataxia, retinal dysplasia, and micro-ophthalmia (Breuss, 2012; Ngo, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2023 | Published functional studies demonstrate impaired neuronal morphology, migration, microtubule assembly, and positioning (Breuss et al., 2012; Ngo et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28347630, 23246003, 24833723, 32085672, 30738969, 28412269) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
D;D;D;D
Polyphen
B;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.0817);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at