rs2571445

Positions:

• chr2-217818431-A-G
• chr2-217818431-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.66 (33990 hom., cov: 34)
  • Exomes 𝑓: 0.61 (272264 hom.)
• Consequence: TNS1 NM_001387777.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.70

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNS1	NM_001387777.1	c.3901T>C	p.Trp1301Arg	missense_variant	24/33	ENST00000682258.1	NP_001374706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNS1	ENST00000682258.1	c.3901T>C	p.Trp1301Arg	missense_variant	24/33		NM_001387777.1	ENSP00000506917.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100438 AN: 152060 Hom.: 33935 Cov.: 34

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

GnomAD3 exomes AF: 0.618 AC: 155050 AN: 251032 Hom.: 48377 AF XY: 0.610 AC XY: 82827 AN XY: 135724

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 SAS exome AF: 0.551

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.: 91 AF XY: 0.607 AC XY: 441328 AN XY: 727094

Gnomad4 AFR exome AF: 0.816

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.578

Gnomad4 SAS exome AF: 0.554

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.618

GnomAD4 genome AF: 0.661 AC: 100553 AN: 152176 Hom.: 33990 Cov.: 34 AF XY: 0.657 AC XY: 48842 AN XY: 74378

Gnomad4 AFR AF: 0.808

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.645

Alfa AF: 0.621 Hom.: 67296

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

Submissions by phenotype

TNS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2022

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.033	.;T;.;T;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.082	T;T;T;T;T;.;T
MetaRNN	Benign	0.0000014	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	.;N;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	3.8	.;N;.;.;.;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	.;T;.;.;.;T;T
Sift4G	Benign	0.52	.;T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;.;B;B
Vest4		0.18, 0.080, 0.078, 0.16, 0.20, 0.20
MutPred		0.18		.;Gain of methylation at W1197 (P = 0.0296);.;.;.;.;.;
MPC		0.22
ClinPred		0.00063	T
GERP RS		3.7
Varity_R		0.072
gMVP		0.33

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: rs2571445; hg19: chr2-218683154; COSMIC: COSV99409925; COSMIC: COSV99409925;