Variant chr10-47220-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3_ModeratePP5

The NM_177987.3(TUBB8):c.1172G>A(p.Arg391His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,106 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TUBB8
NM_177987.3 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.57

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 links:

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ACMG classification

Classification made for transcript

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 chr10-47221-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB8. . Trascript score misZ: 3.4713 (greater than threshold 3.09). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. GenCC has associacion of the gene with oocyte maturation defect 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

PP5

Variant 10-47220-C-T is Pathogenic according to our data. Variant chr10-47220-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977670.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3 link	c.1172G>A	p.Arg391His	missense_variant	4/4	ENST00000568584.6	NP_817124.1	Q3ZCM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBB8	ENST00000568584.6 link	c.1172G>A	p.Arg391His	missense_variant	4/4	1	NM_177987.3	ENSP00000456206.2	Q3ZCM7
TUBB8	ENST00000564130.2 link	c.1070G>A	p.Arg357His	missense_variant	4/4	5		ENSP00000457610.1	Q5SQY0
TUBB8	ENST00000568866.5 link	c.1061G>A	p.Arg354His	missense_variant	3/3	5		ENSP00000457062.1	A0A075B736
TUBB8	ENST00000561967 link	c.*835G>A		3_prime_UTR_variant	4/4	5		ENSP00000454878.1	A0A075B724

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726888

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

0.66

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;.;T

Eigen

Benign

0.036

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.34

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

D;D;D

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.025

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.59

MutPred

0.85

.;.;Loss of MoRF binding (P = 0.0207);

MVP

0.90

ClinPred

0.99

Varity_R

0.29

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over