NM_177987.3:c.1271A>G

Variant names:

• chr10-47121-T-C
• rs1834346707
• NM_177987.3:c.1271A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_177987.3(TUBB8):​c.1271A>G​(p.Gln424Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.67

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]

ENSG00000237297 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.
• PP5: Variant 10-47121-T-C is Pathogenic according to our data. Variant chr10-47121-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977661.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38418928). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.1271A>G	p.Gln424Arg	missense_variant	Exon 4 of 4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.1271A>G	p.Gln424Arg	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:1

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.54
DEOGEN2	Benign	0.024	.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.48	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N;N
Sift	Uncertain	0.013	D;.;.
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.061	.;.;B
Vest4		0.50
MutPred		0.36		.;.;Gain of helix (P = 0.0854);
MVP		0.76
ClinPred		0.83	D
GERP RS		0.11
Varity_R		0.27
gMVP		0.79

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

Other links and lift over

dbSNP: rs1834346707; hg19: chr10-93061;