15-77070905-T-C

Position:

• chr15-77070905-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005724.6(TSPAN3):​c.50A>G​(p.Asn17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000789 in 1,267,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TSPAN3 NM_005724.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

Genes affected

TSPAN3 (HGNC:17752): (tetraspanin 3) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The use of alternate polyadenylation sites has been found for this gene. Multiple alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40438056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN3	NM_005724.6	c.50A>G	p.Asn17Ser	missense_variant	1/7	ENST00000267970.9	NP_005715.1
TSPAN3	NM_198902.3	c.50A>G	p.Asn17Ser	missense_variant	1/6		NP_944492.1
TSPAN3	NM_001168412.2	c.50A>G	p.Asn17Ser	missense_variant	1/6		NP_001161884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN3	ENST00000267970.9	c.50A>G	p.Asn17Ser	missense_variant	1/7	1	NM_005724.6	ENSP00000267970	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.89e-7 AC: 1 AN: 1267904 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 624982

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: 9.93e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The c.50A>G (p.N17S) alteration is located in exon 1 (coding exon 1) of the TSPAN3 gene. This alteration results from a A to G substitution at nucleotide position 50, causing the asparagine (N) at amino acid position 17 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.80	T;T;D;T
Sift4G	Benign	0.31	T;T;D;T
Polyphen		0.0010	B;.;.;.
Vest4		0.45
MutPred		0.82		Gain of glycosylation at N17 (P = 0.0891);Gain of glycosylation at N17 (P = 0.0891);Gain of glycosylation at N17 (P = 0.0891);Gain of glycosylation at N17 (P = 0.0891);
MVP		0.53
MPC		0.53
ClinPred		0.12	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs936085475; hg19: chr15-77363247;