10-47319-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_177987.3(TUBB8):c.1073C>T(p.Pro358Leu) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P358A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 27)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.94

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-47320-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TUBB8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 10-47319-G-A is Pathogenic according to our data. Variant chr10-47319-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977671.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-47319-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.1073C>T	p.Pro358Leu	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.1073C>T	p.Pro358Leu	missense_variant	4/4	1	NM_177987.3	P1
TUBB8	ENST00000564130.2	c.971C>T	p.Pro324Leu	missense_variant	4/4	5
TUBB8	ENST00000568866.5	c.962C>T	p.Pro321Leu	missense_variant	3/3	5
TUBB8	ENST00000561967.1	c.*736C>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	17
Dann	Benign	0.92
Eigen	Benign	0.041
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.4	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.055	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.67
MutPred		0.76		.;.;Loss of catalytic residue at P357 (P = 0.0096);
MVP		0.81
ClinPred		1.0	D
Varity_R		0.67
gMVP		0.95

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: rs1588269791; hg19: chr10-93259;