rs869025272

Variant names:

• chr10-47143-C-T
• rs869025272
• NM_177987.3:c.1249G>A
• TUBB8 p.Asp417Asn

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_177987.3(TUBB8):​c.1249G>A​(p.Asp417Asn) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.56
• Publications: 9 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 6 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, 0.806
• PP5: Variant 10-47143-C-T is Pathogenic according to our data. Variant chr10-47143-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 221269.Status of the report is criteria_provided_single_submitter, 1 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.1249G>A	p.Asp417Asn	missense	Exon 4 of 4	NP_817124.1	Q3ZCM7
	TUBB8	NM_001389618.1		c.1033G>A	p.Asp345Asn	missense	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.1033G>A	p.Asp345Asn	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.1249G>A	p.Asp417Asn	missense	Exon 4 of 4	ENSP00000456206.2	Q3ZCM7
	TUBB8	ENST00000564130.2	TSL:5	c.1147G>A	p.Asp383Asn	missense	Exon 4 of 4	ENSP00000457610.1	Q5SQY0
	TUBB8	ENST00000568866.5	TSL:5	c.1138G>A	p.Asp380Asn	missense	Exon 3 of 3	ENSP00000457062.1	A0A075B736

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000936 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.071
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.49	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0067	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.077	T
PhyloP100		5.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.019	D
Varity_R		0.38
gMVP		0.83

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: rs869025272; hg19: chr10-93083; COSMIC: COSV100226026; COSMIC: COSV100226026;