rs1057520306

Positions:

• chr10-47679-G-A
• chr10-47679-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_177987.3(TUBB8):​c.713C>T​(p.Thr238Met) 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.749
• PP5: Variant 10-47679-G-A is Pathogenic according to our data. Variant chr10-47679-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 378059.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-47679-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.713C>T	p.Thr238Met	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.713C>T	p.Thr238Met	missense_variant	4/4	1	NM_177987.3	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1458750 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 725722

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:2

Pathogenic, no assertion criteria provided	case-control	Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University	Aug 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 10, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.18	.;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	-0.041	T
MutationTaster	Benign	0.85	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.034	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.66
MutPred		0.41		.;.;Gain of stability (P = 0.0992);
MVP		0.69
ClinPred		1.0	D
Varity_R		0.50
gMVP		0.77

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: rs1057520306; hg19: chr10-93619;