chr15-77052866-T-C

Position:

• chr15-77052866-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000267970.9(TSPAN3):​c.496A>G​(p.Lys166Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSPAN3 ENST00000267970.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18

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]

TSPAN3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24940535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN3	NM_005724.6	c.496A>G	p.Lys166Glu	missense_variant	5/7	ENST00000267970.9	NP_005715.1
TSPAN3	NM_198902.3	c.421A>G	p.Lys141Glu	missense_variant	4/6		NP_944492.1
TSPAN3	NM_001168412.2	c.304A>G	p.Lys102Glu	missense_variant	4/6		NP_001161884.1
TSPAN3	XM_017021857.2	c.379A>G	p.Lys127Glu	missense_variant	5/7		XP_016877346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN3	ENST00000267970.9	c.496A>G	p.Lys166Glu	missense_variant	5/7	1	NM_005724.6	ENSP00000267970.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

Apr 13, 2022

The c.496A>G (p.K166E) alteration is located in exon 5 (coding exon 5) of the TSPAN3 gene. This alteration results from a A to G substitution at nucleotide position 496, causing the lysine (K) at amino acid position 166 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;.;.;T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.89	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.69	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.088	T;D;D;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.024	B;.;.;.
Vest4		0.45
MutPred		0.48		Loss of methylation at K166 (P = 0.0063);.;.;.;
MVP		0.49
MPC		0.95
ClinPred		0.77	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.88

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: rs893801570; hg19: chr15-77345208;