rs11558747

Positions:

• chr15-63059674-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018005.2(TPM1):​c.486T>C​(p.Tyr162=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,607,220 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (246 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2839 hom.)
• Consequence: TPM1 NM_001018005.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-63059674-T-C is Benign according to our data. Variant chr15-63059674-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 31889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63059674-T-C is described in Lovd as [Benign]. Variant chr15-63059674-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.486T>C	p.Tyr162=	synonymous_variant	4/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.486T>C	p.Tyr162=	synonymous_variant	4/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7428 AN: 152090 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0541 AC: 13604 AN: 251316 Hom.: 541 AF XY: 0.0548 AC XY: 7447 AN XY: 135834

Gnomad AFR exome AF: 0.00973

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0192

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.0715

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0580 AC: 84429 AN: 1455012 Hom.: 2839 Cov.: 30 AF XY: 0.0574 AC XY: 41563 AN XY: 724130

Gnomad4 AFR exome AF: 0.00996

Gnomad4 AMR exome AF: 0.0356

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0984

Gnomad4 NFE exome AF: 0.0621

Gnomad4 OTH exome AF: 0.0577

GnomAD4 genome AF: 0.0487 AC: 7419 AN: 152208 Hom.: 246 Cov.: 32 AF XY: 0.0496 AC XY: 3692 AN XY: 74430

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.0589

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0983

Gnomad4 NFE AF: 0.0651

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.0620 Hom.: 195

Bravo AF: 0.0445

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0733

EpiControl AF: 0.0745

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2016	p.Tyr162Tyr in exon 4 of TPM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8% (5101/66566) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs11558747). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2011	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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2018	- -

Hypertrophic cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 29, 2022	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -

Hypertrophic cardiomyopathy 3 Benign:1

Benign, 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 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. -

Dilated cardiomyopathy 1Y Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11558747; hg19: chr15-63351873; COSMIC: COSV51261387; COSMIC: COSV51261387;