rs148025238

chr10-47792-A-Cchr10-47792-A-Gchr10-47792-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_177987.3(TUBB8):c.600T>G(p.Phe200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 36)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TUBB8
• BP4: Computational evidence support a benign effect (MetaRNN=0.24854156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.600T>G	p.Phe200Leu	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.600T>G	p.Phe200Leu	missense_variant	4/4	1	NM_177987.3	P1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 36

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Female infertility Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, Nadiya Clinic of Reproductive Medicine

Jan 22, 2018

The variant NM_177987.2(TUBB8):c.600T>G (p.(Phe200Leu)) was not reported previously. It is absent from gnomAD Exomes (ExAC) database, considering that 99.15% of samples have the site covered more than 20 times and mean coverage is 96.8. The variant is located in the tubulin domain (PF00091), which is critical for the protein’s function. All reported variants in this domain are known to be involved in defective oocyte maturation. As of today, all reported missense variants in TUBB8 are known to be associated with the oocyte maturation defect 2 (OOMD2, OMIM:616780) and only a few pathologic variants are not missense. This is a conservative missense variant. In silico predictions are mostly benign or neutral. Therefore, we consider this variant to be of uncertain significance due to the conflicting evidence. Hopefully, a body of evidence will grow, enabling more precise classification. It should be noted that clinical observations in our case do not fully match OOMD2 phenotype (OMIM:616780), but rather resemble PREMBL2 phenotype (OMIM:617234) that is known to be caused by mutations in PADI6. The ICSI-IVF cycle, that was carried out after 3 failed IUI cycles, resulted in retrieval of 28 oocytes: 2 degenerated, 3 in GV stage, 2 in MI stage and 21 in MII stage. Out of 23 oocytes that underwent ICSI (MII and MI), only 13 developed 2 pronuclei; the zygotes subsequently underwent early embryonic arrest. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	12
Dann	Benign	0.32
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D;D
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.27	.;.;B
Vest4		0.25
MutPred		0.33		.;.;Loss of catalytic residue at N204 (P = 0.1726);
MVP		0.59
ClinPred		0.71	D
Varity_R		0.61
gMVP		0.41

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: rs148025238; hg19: chr10-93732;