10-47143-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3 PP5_Moderate

The NM_177987.3(TUBB8):c.1249G>A(p.Asp417Asn) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D417Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.56

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 chr10-47143-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TUBB8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 10-47143-C-T is Pathogenic according to our data. Variant chr10-47143-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 221269.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-47143-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.1249G>A	p.Asp417Asn	missense_variant	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.1249G>A	p.Asp417Asn	missense_variant	4/4	1	NM_177987.3	P1
TUBB8	ENST00000564130.2	c.1147G>A	p.Asp383Asn	missense_variant	4/4	5
TUBB8	ENST00000568866.5	c.1138G>A	p.Asp380Asn	missense_variant	3/3	5
TUBB8	ENST00000561967.1	c.*912G>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 10, 2023	- -
Pathogenic, criteria provided, single submitter	literature only	SNPedia	Jan 21, 2016	Infertility, female -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	0.071
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.49	N
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.077	T
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;N;N
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.83
MutPred		0.71		.;.;Loss of phosphorylation at S420 (P = 0.1573);
MVP		0.78
ClinPred		0.97	D
Varity_R		0.38
gMVP		0.83

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: rs869025272; hg19: chr10-93083; COSMIC: COSV100226026; COSMIC: COSV100226026;