10-47359-G-A

Position:

• chr10-47359-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_177987.3(TUBB8):​c.1033C>T​(p.Leu345Phe) variant causes a missense change. 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 no classification for the single variant (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 27)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40017384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.1033C>T	p.Leu345Phe	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.1033C>T	p.Leu345Phe	missense_variant	4/4	1	NM_177987.3	ENSP00000456206.2
TUBB8	ENST00000564130.2	c.931C>T	p.Leu311Phe	missense_variant	4/4	5		ENSP00000457610.1
TUBB8	ENST00000568866.5	c.922C>T	p.Leu308Phe	missense_variant	3/3	5		ENSP00000457062.1
TUBB8	ENST00000561967	c.*696C>T		3_prime_UTR_variant	4/4	5		ENSP00000454878.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.28	.;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.72	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N;N
Sift	Benign	0.049	D;.;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.0060	.;.;B
Vest4		0.17
MutPred		0.27		.;.;Gain of catalytic residue at L345 (P = 0.069);
MVP		0.69
ClinPred		0.54	D
Varity_R		0.57
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: rs4880608; hg19: chr10-93299;