rs144045691

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001365778.1(TPM1):c.901A>G(p.Lys301Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

TPM1
NM_001365778.1 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 9.11

Variant links:

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1 links:

ENSG00000259627 (HGNC:):

ENSG00000259627 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the TPM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 2.8677 (below the threshold of 3.09). Trascript score misZ: 3.593 (above the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

BP4

Computational evidence support a benign effect (MetaRNN=0.008403361).

BP6

Variant 15-63071092-A-G is Benign according to our data. Variant chr15-63071092-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43687.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr15-63071092-A-G is described in Lovd as [Benign]. Variant chr15-63071092-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0005 (731/1461770) while in subpopulation NFE AF= 0.000341 (379/1111954). AF 95% confidence interval is 0.000312. There are 0 homozygotes in gnomad4_exome. There are 355 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
TPM1	NM_001365778.1 link	c.901A>G	p.Lys301Glu	missense_variant, splice_region_variant	Exon 10 of 10	NP_001352707.1
TPM1	NM_001407326.1 link	c.854A>G	p.Glu285Gly	missense_variant, splice_region_variant	Exon 10 of 10	NP_001394255.1
TPM1	NM_001018004.2 link	c.775A>G	p.Lys259Glu	missense_variant, splice_region_variant	Exon 9 of 9	NP_001018004.1	P09493-9O15513

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TPM1	ENST00000267996.11 link	c.775A>G	p.Lys259Glu	missense_variant, splice_region_variant	Exon 9 of 9	1	ENSP00000267996.7	P09493-7
TPM1	ENST00000358278.7 link	c.775A>G	p.Lys259Glu	missense_variant, splice_region_variant	Exon 9 of 9	1	ENSP00000351022.3	P09493-3
TPM1	ENST00000404484.9 link	c.667A>G	p.Lys223Glu	missense_variant, splice_region_variant	Exon 8 of 8	1	ENSP00000384315.4	H7BYY1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000815

AC:

203

AN:

248946

Hom.:

AF XY:

0.000757

AC XY:

102

AN XY:

134754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00490

Gnomad NFE exome

AF:

0.000800

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000500

AC:

731

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

355

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00597

Gnomad4 NFE exome

AF:

0.000341

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000505

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00508

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000906

AC:

110

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Sep 21, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lys259Glu in exon 10 of TPM1: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (3/186) of Finnish chromosomes b y the 1000 genomes project (rs144045691). At this frequency it is unlikely disea se causing though a modifying role cannot be excluded. Lys259Glu in exon 10 of TPM1 (rs144045691; allele frequency = 1.6%, 3/186) -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 04, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23785128, 28798025, 30847666) -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Nov 19, 2013

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Jun 18, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TPM1-related disorder

Benign:1

Aug 19, 2019

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.48

.;T;.;.;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;D;D;D;D;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0084

T;T;T;T;T;T

MetaSVM

Benign

-0.84

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.49

N;N;N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.73

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;.;.

Vest4

0.64

MVP

0.69

MPC

1.7

ClinPred

0.12

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

gMVP

0.82

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over