NM_177987.3:c.600T>A

Variant names:

• chr10-47792-A-T
• rs148025238
• NM_177987.3:c.600T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_177987.3(TUBB8):​c.600T>A​(p.Phe200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 36)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• 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: AR, SD, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24507359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.600T>A	p.Phe200Leu	missense_variant	Exon 4 of 4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.600T>A	p.Phe200Leu	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 36

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.36
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.64	T
PhyloP100		1.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D;D
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.27	.;.;B
Vest4		0.25
MutPred		0.33		.;.;Loss of catalytic residue at N204 (P = 0.1726);
MVP		0.59
ClinPred		0.71	D
Varity_R		0.61
gMVP		0.41
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: rs148025238; hg19: chr10-93732;