10-47549-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1 BS1_Supporting

The NM_177987.3(TUBB8):c.843C>G(p.Tyr281Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 139,686 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 not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 stop_gained
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.25

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 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00214 (299/139686) while in subpopulation SAS AF= 0.00288 (13/4510). AF 95% confidence interval is 0.00231. There are 0 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB8	NM_177987.3	c.843C>G	p.Tyr281Ter	stop_gained	4/4	ENST00000568584.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB8	ENST00000568584.6	c.843C>G	p.Tyr281Ter	stop_gained	4/4	1	NM_177987.3	P1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 298 AN: 139572 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00272

Gnomad AMI AF: 0.00255

Gnomad AMR AF: 0.00265

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00287

Gnomad FIN AF: 0.000791

Gnomad MID AF: 0.0116

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000193 AC: 46 AN: 238432 Hom.: 0 AF XY: 0.000184 AC XY: 24 AN XY: 130774

Gnomad AFR exome AF: 0.000365

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000234

Gnomad OTH exome AF: 0.000522

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000389 AC: 537 AN: 1382196 Hom.: 0 Cov.: 33 AF XY: 0.000380 AC XY: 261 AN XY: 687340

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.000423

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.000984

Gnomad4 NFE exome AF: 0.000333

Gnomad4 OTH exome AF: 0.000519

GnomAD4 genome AF: 0.00214 AC: 299 AN: 139686 Hom.: 0 Cov.: 29 AF XY: 0.00223 AC XY: 153 AN XY: 68496

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00264

Gnomad4 ASJ AF: 0.00233

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00288

Gnomad4 FIN AF: 0.000791

Gnomad4 NFE AF: 0.00189

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0130 Hom.: 0

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

CIC-DUX Sarcoma Other:1

not provided, no classification provided

literature only

Children's Cancer Therapy Development Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Benign	-0.0087
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.43	N
MutationTaster	Benign	1.0	D;D;D;D;D;D
Vest4		0.13

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: rs200311430; hg19: chr10-93489; COSMIC: COSV59114681; COSMIC: COSV59114681;