rs1057520306

Variant names:

• chr10-47679-G-A
• rs1057520306
• NM_177987.3:c.713C>T
• TUBB8 p.Thr238Met

Your query was ambiguous. Multiple possible variants found:

• chr10-47679-G-A
• chr10-47679-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_177987.3(TUBB8):​c.713C>T​(p.Thr238Met) 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.94
• 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: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant 10-47679-G-A is Pathogenic according to our data. Variant chr10-47679-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 378059.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.713C>T	p.Thr238Met	missense	Exon 4 of 4	NP_817124.1	Q3ZCM7
	TUBB8	NM_001389618.1		c.497C>T	p.Thr166Met	missense	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.497C>T	p.Thr166Met	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.713C>T	p.Thr238Met	missense	Exon 4 of 4	ENSP00000456206.2	Q3ZCM7
	TUBB8	ENST00000564130.2	TSL:5	c.611C>T	p.Thr204Met	missense	Exon 4 of 4	ENSP00000457610.1	Q5SQY0
	TUBB8	ENST00000568866.5	TSL:5	c.602C>T	p.Thr201Met	missense	Exon 3 of 3	ENSP00000457062.1	A0A075B736

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1458750 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 725722

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4338

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111312

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.041	T
PhyloP100		6.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Varity_R		0.50
gMVP		0.77

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: rs1057520306;

hg19: chr10-93619;