chr10-47376-C-T

Variant names:

• chr10-47376-C-T
• NM_177987.3:c.1016G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_177987.3(TUBB8):​c.1016G>A​(p.Ser339Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: TUBB8 NM_177987.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB8	NM_177987.3	c.1016G>A	p.Ser339Asn	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.1016G>A	p.Ser339Asn	missense_variant	Exon 4 of 4	1	NM_177987.3	ENSP00000456206.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1016G>A (p.S339N) alteration is located in exon 4 (coding exon 4) of the TUBB8 gene. This alteration results from a G to A substitution at nucleotide position 1016, causing the serine (S) at amino acid position 339 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.30	.;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.066	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N;N;N
Sift	Pathogenic	0.0	D;.;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.70	.;.;P
Vest4		0.51
MutPred		0.57		.;.;Gain of ubiquitination at K336 (P = 0.0725);
MVP		0.84
ClinPred		0.75	D
Varity_R		0.69
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-93316;