chr2-217818431-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001387777.1(TNS1):c.3901T>C(p.Trp1301Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,613,836 control chromosomes in the GnomAD database, including 306,254 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.66 ( 33990 hom., cov: 34)

Exomes 𝑓: 0.61 ( 272264 hom. )

Consequence

TNS1
NM_001387777.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.70

Publications

112 publications found

Variant links:

Genes affected

TNS1 (HGNC:11973): (tensin 1) The protein encoded by this gene localizes to focal adhesions, regions of the plasma membrane where the cell attaches to the extracellular matrix. This protein crosslinks actin filaments and contains a Src homology 2 (SH2) domain, which is often found in molecules involved in signal transduction. This protein is a substrate of calpain II. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

TNS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3957009E-6).

BP6

Variant 2-217818431-A-G is Benign according to our data. Variant chr2-217818431-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060903.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387777.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNS1	NM_001387777.1	MANE Select	c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	NP_001374706.1
TNS1	NM_001438865.1		c.3964T>C	p.Trp1322Arg	missense	Exon 24 of 33	NP_001425794.1
TNS1	NM_001438866.1		c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	NP_001425795.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNS1	ENST00000682258.1	MANE Select	c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	ENSP00000506917.1
TNS1	ENST00000171887.8	TSL:1	c.3589T>C	p.Trp1197Arg	missense	Exon 24 of 33	ENSP00000171887.4
TNS1	ENST00000419504.6	TSL:1	c.3550T>C	p.Trp1184Arg	missense	Exon 23 of 32	ENSP00000408724.1

Frequencies

GnomAD3 genomes

AF:

0.661

AC:

100438

AN:

152060

Hom.:

33935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.808

Gnomad AMI

AF:

0.558

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.654

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.533

Gnomad MID

AF:

0.680

Gnomad NFE

AF:

0.606

Gnomad OTH

AF:

0.645

GnomAD2 exomes

AF:

0.618

AC:

155050

AN:

251032

AF XY:

0.610

show subpopulations

Gnomad AFR exome

AF:

0.812

Gnomad AMR exome

AF:

0.646

Gnomad ASJ exome

AF:

0.653

Gnomad EAS exome

AF:

0.622

Gnomad FIN exome

AF:

0.541

Gnomad NFE exome

AF:

0.610

Gnomad OTH exome

AF:

0.616

GnomAD4 exome

AF:

0.609

AC:

889818

AN:

1461660

Hom.:

272264

Cov.:

AF XY:

0.607

AC XY:

441328

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.816

AC:

27326

AN:

33474

American (AMR)

AF:

0.640

AC:

28621

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.647

AC:

16909

AN:

26132

East Asian (EAS)

AF:

0.578

AC:

22928

AN:

39698

South Asian (SAS)

AF:

0.554

AC:

47786

AN:

86236

European-Finnish (FIN)

AF:

0.549

AC:

29284

AN:

53362

Middle Eastern (MID)

AF:

0.704

AC:

4054

AN:

5762

European-Non Finnish (NFE)

AF:

0.608

AC:

675611

AN:

1111900

Other (OTH)

AF:

0.618

AC:

37299

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

25242

50483

75725

100966

126208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18378

36756

55134

73512

91890

<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:

0.661

AC:

100553

AN:

152176

Hom.:

33990

Cov.:

AF XY:

0.657

AC XY:

48842

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.808

AC:

33560

AN:

41512

American (AMR)

AF:

0.644

AC:

9853

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

2272

AN:

3472

East Asian (EAS)

AF:

0.621

AC:

3210

AN:

5172

South Asian (SAS)

AF:

0.561

AC:

2706

AN:

4820

European-Finnish (FIN)

AF:

0.533

AC:

5644

AN:

10590

Middle Eastern (MID)

AF:

0.704

AC:

207

AN:

294

European-Non Finnish (NFE)

AF:

0.606

AC:

41231

AN:

68004

Other (OTH)

AF:

0.645

AC:

1362

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1752

3504

5256

7008

8760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.629

Hom.:

98412

Bravo

AF:

0.677

TwinsUK

AF:

0.611

AC:

2265

ALSPAC

AF:

0.615

AC:

2372

ESP6500AA

AF:

0.801

AC:

3530

ESP6500EA

AF:

0.614

AC:

5284

ExAC

AF:

0.619

AC:

75169

Asia WGS

AF:

0.606

AC:

2108

AN:

3478

EpiCase

AF:

0.623

EpiControl

AF:

0.617

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TNS1-related disorder

Benign:1

Mar 30, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.033

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.082

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.2

PhyloP100

2.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

3.8

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.18

MutPred

0.18

Gain of methylation at W1197 (P = 0.0296)

MPC

0.22

ClinPred

0.00063

GERP RS

3.7

Varity_R

0.072

gMVP

0.33

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over