chr10-47433-C-T

Position:

• chr10-47433-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PS1_Moderate PM2 PP2 BP4

The NM_177987.3(TUBB8):​c.959G>A​(p.Arg320His) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 28)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

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 4 ACMG points.

• PS1: Transcript NM_177987.3 (TUBB8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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=0.35737994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.959G>A	p.Arg320His	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.959G>A	p.Arg320His	missense_variant	4/4	1	NM_177987.3	ENSP00000456206.2
TUBB8	ENST00000564130.2	c.857G>A	p.Arg286His	missense_variant	4/4	5		ENSP00000457610.1
TUBB8	ENST00000568866.5	c.848G>A	p.Arg283His	missense_variant	3/3	5		ENSP00000457062.1
TUBB8	ENST00000561967	c.*622G>A		3_prime_UTR_variant	4/4	5		ENSP00000454878.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 28

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oocyte maturation defect 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PS3_Supporting+PS4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Uncertain	0.55	.;.;D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.37	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Benign	0.076	T;T;T
Polyphen		0.039	.;.;B
Vest4		0.40
MutPred		0.50		.;.;Loss of MoRF binding (P = 0.0335);
MVP		0.72
ClinPred		0.76	D
Varity_R		0.41
gMVP		0.79

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: rs1465781298; hg19: chr10-93373;