rs869025273

Variant names:

• chr10-49234-C-T
• rs869025273
• NM_177987.3:c.5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_177987.3(TUBB8):​c.5G>A​(p.Arg2Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.84
• Publications: 6 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, SD, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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.
• PP5: Variant 10-49234-C-T is Pathogenic according to our data. Variant chr10-49234-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 221270.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB8	NM_177987.3	MANE Select	c.5G>A	p.Arg2Lys	missense	Exon 1 of 4	NP_817124.1
	TUBB8	NM_001389618.1		c.-160+174G>A		intron	N/A	NP_001376547.1
	TUBB8	NM_001389619.1		c.-160+174G>A		intron	N/A	NP_001376548.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB8	ENST00000568584.6	TSL:1 MANE Select	c.5G>A	p.Arg2Lys	missense	Exon 1 of 4	ENSP00000456206.2
	TUBB8	ENST00000568866.5	TSL:5	c.5G>A	p.Arg2Lys	missense	Exon 1 of 3	ENSP00000457062.1
	TUBB8	ENST00000561967.1	TSL:5	c.5G>A	p.Arg2Lys	missense	Exon 1 of 4	ENSP00000454878.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432942 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 710336

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.00 AC: 0 AN: 41176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 38066

South Asian (SAS) AF: 0.00 AC: 0 AN: 82288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098300

Other (OTH) AF: 0.00 AC: 0 AN: 59212

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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	0.72
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.36	T
PhyloP100		4.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.76	N
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
Polyphen		0.24	B
Vest4		0.80
MutPred		0.47		Gain of ubiquitination at R2 (P = 0.0155)
MVP		0.78
ClinPred		0.94	D
GERP RS		0.11
PromoterAI		0.075	Neutral
Varity_R		0.33
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025273; hg19: chr10-95174;