chr10-47607-C-T

Position:

• chr10-47607-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000568584.6(TUBB8):​c.785G>A​(p.Arg262Gln) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBB8 ENST00000568584.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.57

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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). GenCC has associacion of gene with oocyte maturation defect 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 10-47607-C-T is Pathogenic according to our data. Variant chr10-47607-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 223144.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-47607-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.785G>A	p.Arg262Gln	missense_variant	4/4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.785G>A	p.Arg262Gln	missense_variant	4/4	1	NM_177987.3	ENSP00000456206	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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	0.78
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	.;.;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	0.81	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D;D;D
Sift	Uncertain	0.026	D;.;.
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.91	.;.;P
Vest4		0.63
MutPred		0.95		.;.;Loss of methylation at R262 (P = 0.0266);
MVP		0.90
ClinPred		0.95	D
Varity_R		0.74
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: rs869025610; hg19: chr10-93547;