10-47203-A-C

Variant names:

• chr10-47203-A-C
• rs1834349280
• NM_177987.3:c.1189T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_177987.3(TUBB8):​c.1189T>G​(p.Trp397Gly) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 26)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.49
• Publications: 0 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: SD, AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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, 0.948
• PP5: Variant 10-47203-A-C is Pathogenic according to our data. Variant chr10-47203-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 977655.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.1189T>G	p.Trp397Gly	missense	Exon 4 of 4	NP_817124.1	Q3ZCM7
	TUBB8	NM_001389618.1		c.973T>G	p.Trp325Gly	missense	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.973T>G	p.Trp325Gly	missense	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.1189T>G	p.Trp397Gly	missense	Exon 4 of 4	ENSP00000456206.2	Q3ZCM7
	TUBB8	ENST00000564130.2	TSL:5	c.1087T>G	p.Trp363Gly	missense	Exon 4 of 4	ENSP00000457610.1	Q5SQY0
	TUBB8	ENST00000568866.5	TSL:5	c.1078T>G	p.Trp360Gly	missense	Exon 3 of 3	ENSP00000457062.1	A0A075B736

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Likely 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
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	-0.00045
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.42	D
PhyloP100		6.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.1	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.84		Gain of disorder (P = 0.0064)
MVP		0.84
ClinPred		1.0	D
Varity_R		0.83
gMVP		0.89
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1834349280; hg19: chr10-93143;