12-71139722-T-A

Variant names:

• chr12-71139722-T-A
• rs375610599
• NM_004616.3:c.250A>T

Variant summary

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

The NM_004616.3(TSPAN8):​c.250A>T​(p.Met84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.404

Genes affected

TSPAN8 (HGNC:11855): (tetraspanin 8) 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. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This gene is expressed in different carcinomas. The use of alternate polyadenylation sites has been found for this gene. [provided by RefSeq, Jul 2008]

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=0.18714556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.250A>T	p.Met84Leu	missense_variant	Exon 4 of 9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.250A>T	p.Met84Leu	missense_variant	Exon 3 of 8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN8	ENST00000247829.8	c.250A>T	p.Met84Leu	missense_variant	Exon 4 of 9	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6	c.250A>T	p.Met84Leu	missense_variant	Exon 7 of 12	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2	c.250A>T	p.Met84Leu	missense_variant	Exon 3 of 8	1		ENSP00000447160.1
TSPAN8	ENST00000552786.1	n.*111A>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461450 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250A>T (p.M84L) alteration is located in exon 4 (coding exon 3) of the TSPAN8 gene. This alteration results from a A to T substitution at nucleotide position 250, causing the methionine (M) at amino acid position 84 to be replaced by a leucine (L). 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	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.63	.;.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.68	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.040	B;B;B
Vest4		0.29
MutPred		0.60		Loss of methylation at K79 (P = 0.0803);Loss of methylation at K79 (P = 0.0803);Loss of methylation at K79 (P = 0.0803);
MVP		0.58
MPC		0.093
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.22
gMVP		0.67

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: rs375610599; hg19: chr12-71533502;