dbSNP rs753825850: TSPAN8:p.Gly153Cys (chr12-71132812-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004616.3(TSPAN8):c.457G>T(p.Gly153Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,602 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. G153S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSPAN8
NM_004616.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.61

Publications

0 publications found

Variant links:

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]

TSPAN8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004616.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN8	NM_004616.3	MANE Select	c.457G>T	p.Gly153Cys	missense	Exon 7 of 9	NP_004607.1	P19075
	TSPAN8	NM_001369760.1		c.457G>T	p.Gly153Cys	missense	Exon 6 of 8	NP_001356689.1	P19075

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSPAN8	ENST00000247829.8	TSL:1 MANE Select	c.457G>T	p.Gly153Cys	missense	Exon 7 of 9	ENSP00000247829.3	P19075
TSPAN8	ENST00000393330.6	TSL:1	c.457G>T	p.Gly153Cys	missense	Exon 10 of 12	ENSP00000377003.2	P19075
TSPAN8	ENST00000546561.2	TSL:1	c.457G>T	p.Gly153Cys	missense	Exon 6 of 8	ENSP00000447160.1	P19075

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

PhyloP100

3.6

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.6

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.95

Gain of ubiquitination at K150 (P = 0.0849)

MVP

0.96

MPC

0.49

ClinPred

1.0

GERP RS

5.9

Varity_R

0.94

gMVP

0.96

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over