chr10-47253-C-T

Variant names:

• chr10-47253-C-T
• rs1554738022
• NM_177987.3:c.1139G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_177987.3(TUBB8):​c.1139G>A​(p.Arg380His) 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB8 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 3.4713 (above the threshold of 3.09). GenCC associations: The gene is linked to oocyte maturation defect 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.1139G>A	p.Arg380His	missense_variant	Exon 4 of 4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.1139G>A	p.Arg380His	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461458 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727038

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.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oocyte maturation defect 2 Pathogenic:1 Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP2+PS4_Supporting+PP4 -

Aug 31, 2020

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not provided Uncertain:1

Nov 04, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg380His variant in TUBB8 has been reported in 6 individuals with oocyte maturation defects (Zhao 2020 PMID: 32524331, Zheng 2021 PMID: 33970371, Yang 2021 PMID:33009822). Additionally, this variant was identified through WGS analysis by the Broad Institute Rare Genomes Project in an adult female with infertility, parthenogenic activation of oocytes, and oocyte maturation defects and also in her mother with a history of infertility, fibroids, and recurrent miscarriage. It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 977679). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Uncertain	0.61	.;.;D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.48	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;D;D
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.81	.;.;P
Vest4		0.58
MutPred		0.76		.;.;Loss of MoRF binding (P = 0.0199);
MVP		0.81
ClinPred		0.79	D
Varity_R		0.51
gMVP		0.87

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: rs1554738022; hg19: chr10-93193;