chr10-47253-C-T

Variant summary

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

The NM_177987.3(TUBB8):​c.1139G>A​(p.Arg380His) 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 27)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TUBB8
NM_177987.3 missense

Scores

2
6
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 5.57
Variant links:
Genes affected
TUBB8 (HGNC:20773): (tubulin beta 8 class VIII) The protein encoded by this gene represents the primary beta-tubulin subunit of oocytes and the early embryo. Defects in this gene, which is primate-specific, are a cause of oocyte maturation defect 2 and infertility. [provided by RefSeq, Mar 2016]

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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 the TUBB8 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 3.4713 (above the threshold of 3.09). GenCC associations: The gene is linked to oocyte maturation defect 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TUBB8NM_177987.3 linkc.1139G>A p.Arg380His missense_variant Exon 4 of 4 ENST00000568584.6 NP_817124.1 Q3ZCM7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TUBB8ENST00000568584.6 linkc.1139G>A p.Arg380His missense_variant Exon 4 of 4 1 NM_177987.3 ENSP00000456206.2 Q3ZCM7

Frequencies

GnomAD3 genomes
Cov.:
27
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461458
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727038
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
27

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:1Uncertain:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PP2+PS4_Supporting+PP4 -

Aug 31, 2020
Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control

- -

not provided Uncertain:1
Nov 04, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg380His variant in TUBB8 has been reported in 6 individuals with oocyte maturation defects (Zhao 2020 PMID: 32524331, Zheng 2021 PMID: 33970371, Yang 2021 PMID:33009822). Additionally, this variant was identified through WGS analysis by the Broad Institute Rare Genomes Project in an adult female with infertility, parthenogenic activation of oocytes, and oocyte maturation defects and also in her mother with a history of infertility, fibroids, and recurrent miscarriage. It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 977679). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
19
DANN
Benign
0.89
DEOGEN2
Uncertain
0.61
.;.;D
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.78
T;T;T
M_CAP
Benign
0.050
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Benign
-0.48
T
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.9
D;D;D
Sift
Pathogenic
0.0
D;.;.
Sift4G
Uncertain
0.024
D;D;D
Polyphen
0.81
.;.;P
Vest4
0.58
MutPred
0.76
.;.;Loss of MoRF binding (P = 0.0199);
MVP
0.81
ClinPred
0.79
D
Varity_R
0.51
gMVP
0.87

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: rs1554738022; hg19: chr10-93193; API