rs869025271

Variant names:

• chr10-47706-A-G
• rs869025271
• NM_177987.3:c.686T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_177987.3(TUBB8):​c.686T>C​(p.Val229Ala) 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: 35)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.49
• Publications: 4 publications found

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]

TUBB8 Gene-Disease associations (from GenCC):

• oocyte maturation defect 2

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 10-47706-A-G is Pathogenic according to our data. Variant chr10-47706-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 221268.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.686T>C	p.Val229Ala	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.686T>C	p.Val229Ala	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:2

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	0.70
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.34	T
PhyloP100		6.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D;D
Sift	Uncertain	0.0010	D;.;.
Sift4G	Benign	0.071	T;T;T
Polyphen		0.99	.;.;D
Vest4		0.87
MutPred		0.75		.;.;Gain of disorder (P = 0.0905);
MVP		0.82
ClinPred		0.97	D
Varity_R		0.80
gMVP		0.75

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

Other links and lift over

dbSNP: rs869025271; hg19: chr10-93646;