rs869025609

Variant names:

• chr10-47865-G-A
• rs869025609
• NM_177987.3:c.527C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_177987.3(TUBB8):​c.527C>T​(p.Ser176Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• 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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_177987.3
• 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, 0.868
• PP5: Variant 10-47865-G-A is Pathogenic according to our data. Variant chr10-47865-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 223143.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-47865-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.527C>T	p.Ser176Leu	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.527C>T	p.Ser176Leu	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 80 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 37

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:3

Aug 31, 2020

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Apr 10, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 21, 2016

SNPedia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Infertility, female -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.27	.;.;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.17	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.86
MutPred		0.61		.;.;Loss of disorder (P = 0.0149);
MVP		0.73
ClinPred		1.0	D
Varity_R		0.89
gMVP		0.24

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: rs869025609; hg19: chr10-93805; COSMIC: COSV59114480; COSMIC: COSV59114480;