rs1071646

Positions:

• chr15-63059641-C-A
• chr15-63059641-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001018005.2(TPM1):​c.453C>A​(p.Ala151Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,610,730 control chromosomes in the GnomAD database, including 357,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32801 hom., cov: 31)
  • Exomes 𝑓: 0.66 (324998 hom.)
• Consequence: TPM1 NM_001018005.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 3.42

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-63059641-C-A is Benign according to our data. Variant chr15-63059641-C-A is described in ClinVar as [Benign]. Clinvar id is 31888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63059641-C-A is described in Lovd as [Benign]. Variant chr15-63059641-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.453C>A	p.Ala151Ala	synonymous_variant	4/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.453C>A	p.Ala151Ala	synonymous_variant	4/10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99022 AN: 151884 Hom.: 32785 Cov.: 31

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.670 AC: 168498 AN: 251338 Hom.: 57700 AF XY: 0.674 AC XY: 91516 AN XY: 135852

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.555

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.958

Gnomad SAS exome AF: 0.704

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.652

Gnomad OTH exome AF: 0.674

GnomAD4 exome AF: 0.665 AC: 969963 AN: 1458728 Hom.: 324998 Cov.: 44 AF XY: 0.666 AC XY: 483250 AN XY: 725788

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.563

Gnomad4 ASJ exome AF: 0.665

Gnomad4 EAS exome AF: 0.952

Gnomad4 SAS exome AF: 0.702

Gnomad4 FIN exome AF: 0.698

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.652 AC: 99072 AN: 152002 Hom.: 32801 Cov.: 31 AF XY: 0.656 AC XY: 48748 AN XY: 74284

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.653

Gnomad4 EAS AF: 0.950

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.698

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.639

Alfa AF: 0.656 Hom.: 75761

Bravo AF: 0.646

Asia WGS AF: 0.818 AC: 2845 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.644

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: TPM1 c.453C>A alters a conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.67 in 251338 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 9000 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPM1 causing Cardiomyopathy phenotype (7.5e-05), strongly suggesting that the variant is benign. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -

Dilated cardiomyopathy 1Y Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as 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. -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

TPM1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

This variant is classified as likely 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_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.95

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: rs1071646; hg19: chr15-63351840; COSMIC: COSV51261240; COSMIC: COSV51261240;