rs864321677

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_178014.4(TUBB):​c.665A>T​(p.Tyr222Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y222Y) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TUBB
NM_178014.4 missense

Scores

1
8
8

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.01
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). GenCC has associacion of 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.
PP5
Variant 6-30723727-A-T is Pathogenic according to our data. Variant chr6-30723727-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 218926.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TUBBNM_178014.4 linkuse as main transcriptc.665A>T p.Tyr222Phe missense_variant 4/4 ENST00000327892.13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TUBBENST00000327892.13 linkuse as main transcriptc.665A>T p.Tyr222Phe missense_variant 4/41 NM_178014.4 P1
ENST00000607476.1 linkuse as main transcriptn.151T>A non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Multiple benign circumferential skin creases on limbs 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T;.;T;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Benign
1.7
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.1
D;D;D;D
REVEL
Uncertain
0.42
Sift4G
Benign
0.16
T;T;T;T
Polyphen
0.47
P;.;.;.
Vest4
0.75
MutPred
0.62
Loss of catalytic residue at L217 (P = 0.1155);.;.;.;
MVP
0.87
MPC
1.7
ClinPred
0.97
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3
Varity_R
0.82
gMVP
0.96

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: rs864321677; hg19: chr6-30691504; API