dbSNP rs3763978: TSPAN8:p.Gly73Ala (chr12-71139754-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004616.3(TSPAN8):c.218G>C(p.Gly73Ala) variant causes a missense change. The variant allele was found at a frequency of 0.373 in 1,612,202 control chromosomes in the GnomAD database, including 118,156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 7969 hom., cov: 32)

Exomes 𝑓: 0.38 ( 110187 hom. )

Consequence

TSPAN8
NM_004616.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.68

Publications

45 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057137907).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3 link	c.218G>C	p.Gly73Ala	missense_variant	Exon 4 of 9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1 link	c.218G>C	p.Gly73Ala	missense_variant	Exon 3 of 8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TSPAN8	ENST00000247829.8 link	c.218G>C	p.Gly73Ala	missense_variant	Exon 4 of 9	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6 link	c.218G>C	p.Gly73Ala	missense_variant	Exon 7 of 12	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2 link	c.218G>C	p.Gly73Ala	missense_variant	Exon 3 of 8	1		ENSP00000447160.1
TSPAN8	ENST00000552786.1 link	n.*79G>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44603

AN:

151926

Hom.:

7967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0925

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.429

Gnomad EAS

AF:

0.304

Gnomad SAS

AF:

0.277

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.408

Gnomad OTH

AF:

0.327

GnomAD2 exomes

AF:

0.329

AC:

82526

AN:

250554

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.0854

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.411

Gnomad EAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.414

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.381

AC:

556859

AN:

1460158

Hom.:

110187

Cov.:

AF XY:

0.381

AC XY:

276909

AN XY:

726328

show subpopulations

African (AFR)

AF:

0.0820

AC:

2744

AN:

33452

American (AMR)

AF:

0.186

AC:

8293

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.423

AC:

11036

AN:

26090

East Asian (EAS)

AF:

0.311

AC:

12325

AN:

39650

South Asian (SAS)

AF:

0.291

AC:

25001

AN:

86000

European-Finnish (FIN)

AF:

0.354

AC:

18898

AN:

53344

Middle Eastern (MID)

AF:

0.383

AC:

2205

AN:

5756

European-Non Finnish (NFE)

AF:

0.409

AC:

454653

AN:

1110890

Other (OTH)

AF:

0.360

AC:

21704

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

17686

35372

53059

70745

88431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13728

27456

41184

54912

68640

<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

AF:

0.293

AC:

44601

AN:

152044

Hom.:

7969

Cov.:

AF XY:

0.290

AC XY:

21544

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0923

AC:

3833

AN:

41524

American (AMR)

AF:

0.249

AC:

3801

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

1486

AN:

3466

East Asian (EAS)

AF:

0.304

AC:

1569

AN:

5160

South Asian (SAS)

AF:

0.279

AC:

1341

AN:

4808

European-Finnish (FIN)

AF:

0.336

AC:

3554

AN:

10564

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.408

AC:

27756

AN:

67952

Other (OTH)

AF:

0.324

AC:

684

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1483

2967

4450

5934

7417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.379

Hom.:

3840

Bravo

AF:

0.280

TwinsUK

AF:

0.410

AC:

1521

ALSPAC

AF:

0.418

AC:

1612

ESP6500AA

AF:

0.110

AC:

483

ESP6500EA

AF:

0.410

AC:

3526

ExAC

AF:

0.333

AC:

40448

Asia WGS

AF:

0.254

AC:

881

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;.;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-1.7

MutationAssessor

Pathogenic

3.6

H;H;H

PhyloP100

4.7

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.67

Sift

Benign

0.033

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.26

MPC

0.47

ClinPred

0.055

GERP RS

5.1

Varity_R

0.72

gMVP

0.93

Mutation Taster

=95/5

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over