rs397516395

Positions:

chr15-63064136-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001018005.2(TPM1):c.845C>G(p.Thr282Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,924 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 7.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 61 pathogenic changes around while only 1 benign (98%) in NM_001018005.2

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.016288191).

BP6

Variant 15-63064136-C-G is Benign according to our data. Variant chr15-63064136-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43449.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr15-63064136-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000125 (19/152352) while in subpopulation SAS AF= 0.00311 (15/4828). AF 95% confidence interval is 0.00191. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.845C>G	p.Thr282Ser	missense_variant	9/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.845C>G	p.Thr282Ser	missense_variant	9/10	1	NM_001018005.2	ENSP00000385107	A1	P09493-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152234

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:

0.00310

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

250636

Hom.:

AF XY:

0.000325

AC XY:

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1461572

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000125

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74502

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:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr282Ser (c.845C>G) in the TPM1 gene was identified. This variant is novel. It has not been reported in association with disease nor as a common polymorphism. This is a conserved amino acid change of a polar Threonine replaced with a polar Serine. Threonine is highly conserved across species at position 282 in the TPM1 gene. A variant in a neighboring codon (Met281Thr) has been reported in association with Hypertrophic Cardiomyopathy (van Driest et al 2003). There are no other reported variants associated with disease in this region. In silico analysis predicts the amino acid change to be benign to protein function (PolyPhen 2). This variant was not observed in 100 presumably healthy control individuals of Caucasian descent at GeneDx. Additionally GeneDx did note the presence of the variant in a patient who was tested for HCM, this individual also carried a disease causing variant in a different sarcomere gene. The variant is not listed in either dbSNP or 1000 genomes (as of July 5th, 2011). -

Hypertrophic cardiomyopathy 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dilated cardiomyopathy 1Y

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 05, 2018

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2019

This variant is associated with the following publications: (PMID: 26265630) -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

CardioboostCm

Benign

0.0083

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

.;D;.;.;.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.016

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.7

L;L;L;.;.;.

MutationTaster

Benign

0.85

D;D;D;D;D;D;D;D;D;D;D;D

PROVEAN

Benign

-0.55

N;N;.;.;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.39

T;T;.;.;.;T

Sift4G

Benign

0.38

T;T;.;.;.;T

Polyphen

0.0, 0.0010

.;B;B;.;.;.

Vest4

0.67

MutPred

0.49

Gain of disorder (P = 0.0313);Gain of disorder (P = 0.0313);Gain of disorder (P = 0.0313);Gain of disorder (P = 0.0313);.;.;

MVP

0.94

ClinPred

0.093

GERP RS

5.8

Varity_R

0.27

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

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