rs869025611

chr10-47304-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_177987.3(TUBB8):c.1088T>C(p.Met363Thr) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.49

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUBB8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 10-47304-A-G is Pathogenic according to our data. Variant chr10-47304-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 223145.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-47304-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.1088T>C	p.Met363Thr	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.1088T>C	p.Met363Thr	missense_variant	4/4	1	NM_177987.3	P1
TUBB8	ENST00000564130.2	c.986T>C	p.Met329Thr	missense_variant	4/4	5
TUBB8	ENST00000568866.5	c.977T>C	p.Met326Thr	missense_variant	3/3	5
TUBB8	ENST00000561967.1	c.*751T>C		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

SNPedia

Jan 21, 2016

Infertility, female -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	16
Dann	Benign	0.55
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.43	D
MutationTaster	Benign	0.71	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.029	D;D;T
Polyphen		0.99	.;.;D
Vest4		0.89
MutPred		0.80		.;.;Loss of sheet (P = 0.1398);
MVP		0.87
ClinPred		0.98	D
Varity_R		0.88
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

Other links and lift over

dbSNP: rs869025611; hg19: chr10-93244;