10-47679-G-T

Position:

• chr10-47679-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_177987.3(TUBB8):​c.713C>A​(p.Thr238Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,458,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. T238M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-47679-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB8. . Trascript score misZ 3.4713 (greater than threshold 3.09). GenCC has associacion of gene with oocyte maturation defect 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.713C>A	p.Thr238Lys	missense_variant	4/4	ENST00000568584.6	NP_817124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB8	ENST00000568584.6	c.713C>A	p.Thr238Lys	missense_variant	4/4	1	NM_177987.3	ENSP00000456206	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458758 Hom.: 0 Cov.: 57 AF XY: 0.00000138 AC XY: 1 AN XY: 725726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.21	.;.;T
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.067	T
MutationTaster	Benign	0.92	D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;D;D
Sift	Uncertain	0.014	D;.;.
Sift4G	Uncertain	0.056	T;D;D
Polyphen		1.0	.;.;D
Vest4		0.76
MutPred		0.43		.;.;Gain of methylation at T238 (P = 0.0079);
MVP		0.71
ClinPred		0.98	D
Varity_R		0.76
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057520306; hg19: chr10-93619;