10-47150-G-C

Position:

• chr10-47150-G-C

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.1242C>G​(p.Asn414Lys) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.12

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). 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, 0.752
• PP5: Variant 10-47150-G-C is Pathogenic according to our data. Variant chr10-47150-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977660.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	c.1242C>G	p.Asn414Lys	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.1242C>G	p.Asn414Lys	missense_variant	4/4	1	NM_177987.3	ENSP00000456206.2
TUBB8	ENST00000564130.2	c.1140C>G	p.Asn380Lys	missense_variant	4/4	5		ENSP00000457610.1
TUBB8	ENST00000568866.5	c.1131C>G	p.Asn377Lys	missense_variant	3/3	5		ENSP00000457062.1
TUBB8	ENST00000561967	c.*905C>G		3_prime_UTR_variant	4/4	5		ENSP00000454878.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.029	.;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.0030	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;N;N
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.043	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.65
MutPred		0.53		.;.;Gain of ubiquitination at N414 (P = 0.0077);
MVP		0.81
ClinPred		0.98	D
Varity_R		0.60
gMVP		0.89

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: rs1834347552; hg19: chr10-93090;