chr10-47452-C-A

Position:

• chr10-47452-C-A

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.940G>T​(p.Ala314Ser) 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. 11/18 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: 28)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.57

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]

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 gene, where missense usually causes diseases (based on misZ statistic), TUBB8. . Trascript score misZ: 3.4713 (greater than threshold 3.09). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. GenCC has associacion of the gene with oocyte maturation defect 2.
• PP5: Variant 10-47452-C-A is Pathogenic according to our data. Variant chr10-47452-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977681.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3868385). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.940G>T	p.Ala314Ser	missense_variant	4/4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.940G>T	p.Ala314Ser	missense_variant	4/4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Aug 31, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.23	.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	-0.13	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N;N
Sift	Uncertain	0.0090	D;.;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.41	.;.;B
Vest4		0.45
MutPred		0.39		.;.;Gain of sheet (P = 0.0827);
MVP		0.87
ClinPred		0.54	D
Varity_R		0.54
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs781859520; hg19: chr10-93392;