rs869025609

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.94

Publications

9 publications found

Variant links:

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)

TUBB8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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, 3 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 VariationId is 223143.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 link	c.527C>T	p.Ser176Leu	missense_variant	Exon 4 of 4	ENST00000568584.6	NP_817124.1	Q3ZCM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6 link	c.527C>T	p.Ser176Leu	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2		Q3ZCM7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

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

- -

Jan 21, 2016

SNPedia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Infertility, female -

Apr 10, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.27

.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.65

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.010

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.17

PhyloP100

6.9

PrimateAI

Uncertain

0.66

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

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over