10-47452-C-G

Variant names:

• chr10-47452-C-G
• rs781859520
• NM_177987.3:c.940G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_177987.3(TUBB8):​c.940G>C​(p.Ala314Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A314S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-47452-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 977681.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

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.940G>C	p.Ala314Pro	missense	Exon 4 of 4	NP_817124.1	Q3ZCM7
	TUBB8	NM_001389618.1		c.724G>C	p.Ala242Pro	missense	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.724G>C	p.Ala242Pro	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.940G>C	p.Ala314Pro	missense	Exon 4 of 4	ENSP00000456206.2	Q3ZCM7
	TUBB8	ENST00000564130.2	TSL:5	c.838G>C	p.Ala280Pro	missense	Exon 4 of 4	ENSP00000457610.1	Q5SQY0
	TUBB8	ENST00000568866.5	TSL:5	c.829G>C	p.Ala277Pro	missense	Exon 3 of 3	ENSP00000457062.1	A0A075B736

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.000158 AC: 39 AN: 246374 AF XY: 0.000164

Gnomad AFR exome AF: 0.000345

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000333

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 6 AN: 1459722 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 726208

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

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.0000942 AC: 5 AN: 53052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ExAC AF: 0.000638 AC: 76

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.42	D
PhyloP100		5.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.47		Loss of MoRF binding (P = 0.0573)
MVP		0.80
ClinPred		0.15	T
Varity_R		0.97
gMVP		0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781859520; hg19: chr10-93392;