NM_001070.5:c.275A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_001070.5(TUBG1):​c.275A>G​(p.Tyr92Cys) 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TUBG1
NM_001070.5 missense

Scores

13
5
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.26
Variant links:
Genes affected
TUBG1 (HGNC:12417): (tubulin gamma 1) This gene encodes a member of the tubulin superfamily. The encoded protein localizes to the centrosome where it binds to microtubules as part of a complex referred to as the gamma-tubulin ring complex. The protein mediates microtubule nucleation and is required for microtubule formation and progression of the cell cycle. A pseudogene of this gene is found on chromosome 7. [provided by RefSeq, Jan 2009]
RETREG3 (HGNC:27258): (reticulophagy regulator family member 3) Involved in positive regulation of neuron projection development. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the TUBG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 4.1551 (above the threshold of 3.09). Trascript score misZ: 5.8568 (above the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly spectrum disorders, complex cortical dysplasia with other brain malformations 4.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
PP5
Variant 17-42610535-A-G is Pathogenic according to our data. Variant chr17-42610535-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65398.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TUBG1NM_001070.5 linkc.275A>G p.Tyr92Cys missense_variant Exon 3 of 11 ENST00000251413.8 NP_001061.2 P23258

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TUBG1ENST00000251413.8 linkc.275A>G p.Tyr92Cys missense_variant Exon 3 of 11 1 NM_001070.5 ENSP00000251413.2 P23258

Frequencies

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

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 4 Pathogenic:2
Jul 30, 2024
Department of Human Genetics, Hannover Medical School
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.5
H;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.0
D;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.012
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.51
Loss of phosphorylation at Y92 (P = 0.0561);Loss of phosphorylation at Y92 (P = 0.0561);
MVP
0.86
MPC
3.2
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.98

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: rs398123046; hg19: chr17-40762553; API