rs869025273

chr10-49234-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_177987.3(TUBB8):c.5G>A(p.Arg2Lys) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.84

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 9 ACMG points.

• PM1: In a short_sequence_motif MREI motif (size 3) in uniprot entity TBB8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_177987.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-49234-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TUBB8
• PP5: Variant 10-49234-C-T is Pathogenic according to our data. Variant chr10-49234-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 221270.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-49234-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.5G>A	p.Arg2Lys	missense_variant	1/4	ENST00000568584.6
TUBB8	NM_001389618.1	c.-160+174G>A		intron_variant
TUBB8	NM_001389619.1	c.-160+174G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.5G>A	p.Arg2Lys	missense_variant	1/4	1	NM_177987.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432942 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 710336

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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	0.72
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Benign	0.83
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.76	N;N;N;N
Sift4G	Uncertain	0.053	T;T;D;D
Polyphen		0.24	.;B;.;.
Vest4		0.80
MutPred		0.47		Gain of ubiquitination at R2 (P = 0.0155);Gain of ubiquitination at R2 (P = 0.0155);Gain of ubiquitination at R2 (P = 0.0155);Gain of ubiquitination at R2 (P = 0.0155);
MVP		0.78
ClinPred		0.94	D
GERP RS		0.11
Varity_R		0.33
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025273; hg19: chr10-95174;