rs267607164
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_006086.4(TUBB3):c.1249G>A(p.Asp417Asn) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
TUBB3
NM_006086.4 missense
NM_006086.4 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 9.92
Genes affected
TUBB3 (HGNC:20772): (tubulin beta 3 class III) This gene encodes a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 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), TUBB3. . Gene score misZ 4.5786 (greater than the threshold 3.09). Trascript score misZ 5.665 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, complex cortical dysplasia with other brain malformations 1, congenital fibrosis of extraocular muscles, fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
Variant 16-89935700-G-A is Pathogenic according to our data. Variant chr16-89935700-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TUBB3 | NM_006086.4 | c.1249G>A | p.Asp417Asn | missense_variant | 4/4 | ENST00000315491.12 | NP_006077.2 | |
TUBB3 | NM_001197181.2 | c.1033G>A | p.Asp345Asn | missense_variant | 4/4 | NP_001184110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TUBB3 | ENST00000315491.12 | c.1249G>A | p.Asp417Asn | missense_variant | 4/4 | 1 | NM_006086.4 | ENSP00000320295.7 | ||
ENSG00000198211 | ENST00000556922.1 | c.2290G>A | p.Asp764Asn | missense_variant | 5/5 | 2 | ENSP00000451560.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2010 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 03, 2021 | This sequence change replaces aspartic acid with asparagine at codon 417 of the TUBB3 protein (p.Asp417Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with axonal peripheral neuropathy and/or congenital fibrosis of the extraocular muscles (PMID: 24257358, 25482575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6966). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. - |
Complex cortical dysplasia with other brain malformations 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2024 | Variant summary: TUBB3 c.1249G>A (p.Asp417Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes. c.1249G>A has been reported in the literature in multiple individuals affected with Cortical Dysplasia, Complex, With Other Brain Malformations 1 (example, Tischfield_ 2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal funciton (Huang_2018, Tischfield_ 2010). The following publications have been ascertained in the context of this evaluation (PMID: 29382549, 20074521). ClinVar contains an entry for this variant (Variation ID: 6966). Based on the evidence outlined above, the variant was classified as pathogenic. - |
TUBB3-related tubulinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Mar 12, 2024 | The heterozygous p.Asp417Asn variant in TUBB3 was identified by our study in one individual with congenital fibrosis of the extraocular muscles. This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. The p.Asp417Asn variant in TUBB3 has been previously reported in at least 7 unrelated individuals with congenital fibrosis of extraocular muscles 3A with or without extraocular involvement (PMID: 24257358, PMID: 25482575, PMID: 20074521, PMID: 34418069) and segregated with disease in 17 affected relatives from 4 families (PMID: 24257358, PMID: 25482575, PMID: 20074521). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in one individual with confirmed paternity and maternity (PMID: 20074521). This variant has also been reported in ClinVar (Variation ID: 6966) and has been interpreted as pathogenic by Invitae and OMIM. This variant was absent from large population studies. The number of missense variants reported in TUBB3 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. The p.Asp417 variant is located in a region of TUBB3 that is essential to interactions with other motor proteins, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 20074521). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp417His, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 20301522, Variation ID: 6965). In vitro functional studies provide some evidence that the p.Asp417Asn variant may impact protein function (PMID:31226147, PMID: 29382549). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital fibrosis of extraocular muscles 3A with or without extraocular involvement. ACMG/AMP Criteria applied: PS2_Supporting, PS3_Supporting, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1_Strong (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;L
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;N;N
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;.;D
Vest4
MutPred
0.81
.;.;Loss of phosphorylation at S420 (P = 0.1618);
MVP
MPC
2.6
ClinPred
D
GERP RS
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