10-47220-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_177987.3(TUBB8):c.1172G>A(p.Arg391His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-47221-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TUBB8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 10-47220-C-T is Pathogenic according to our data. Variant chr10-47220-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977670.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.1172G>A	p.Arg391His	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.1172G>A	p.Arg391His	missense_variant	4/4	1	NM_177987.3	P1
TUBB8	ENST00000564130.2	c.1070G>A	p.Arg357His	missense_variant	4/4	5
TUBB8	ENST00000568866.5	c.1061G>A	p.Arg354His	missense_variant	3/3	5
TUBB8	ENST00000561967.1	c.*835G>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461106 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726888

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

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	0.66
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	0.036
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	0.93	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.59
MutPred		0.85		.;.;Loss of MoRF binding (P = 0.0207);
MVP		0.90
ClinPred		0.99	D
Varity_R		0.29
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: rs1834349844; hg19: chr10-93160;