10-47965-TC-TCC

Variant names:

• chr10-47965-T-TC
• rs782246853
• NM_177987.3:c.426dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_177987.3(TUBB8):​c.426dupG​(p.Thr143AspfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.360
• Publications: 3 publications found

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]

TUBB8 Gene-Disease associations (from GenCC):

• oocyte maturation defect 2

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-47965-T-TC is Pathogenic according to our data. Variant chr10-47965-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 378061.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177987.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB8	NM_177987.3	MANE Select	c.426dupG	p.Thr143AspfsTer12	frameshift	Exon 4 of 4	NP_817124.1	Q3ZCM7
	TUBB8	NM_001389618.1		c.210dupG	p.Thr71AspfsTer12	frameshift	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.210dupG	p.Thr71AspfsTer12	frameshift	Exon 5 of 5	NP_001376548.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB8	ENST00000568584.6	TSL:1 MANE Select	c.426dupG	p.Thr143AspfsTer12	frameshift	Exon 4 of 4	ENSP00000456206.2	Q3ZCM7
	TUBB8	ENST00000564130.2	TSL:5	c.324dupG	p.Thr109AspfsTer12	frameshift	Exon 4 of 4	ENSP00000457610.1	Q5SQY0
	TUBB8	ENST00000568866.5	TSL:5	c.315dupG	p.Thr106AspfsTer12	frameshift	Exon 3 of 3	ENSP00000457062.1	A0A075B736

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251274 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000958 AC: 14 AN: 1461744 Hom.: 0 Cov.: 103 AF XY: 0.0000110 AC XY: 8 AN XY: 727178

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000451758), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 40

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Oocyte maturation defect 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782246853;

hg19: chr10-93905;