rs730881128

Variant names:

Variant summary

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

The NM_001365776.1(TPM1):c.803G>A(p.Arg268His) variant causes a missense change. The variant allele was found at a frequency of 0.0000737 in 1,613,912 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 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

TPM1
NM_001365776.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 5.34

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: 3.6469 (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=0.019482523).

BP6

Variant 15-63069900-G-A is Benign according to our data. Variant chr15-63069900-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181654.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000592 (9/152130) while in subpopulation AMR AF= 0.000589 (9/15274). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
TPM1	NM_001365776.1 link	c.803G>A	p.Arg268His	missense_variant	Exon 9 of 9	NP_001352705.1
TPM1	NM_001407336.1 link	c.803G>A	p.Arg268His	missense_variant	Exon 9 of 9	NP_001394265.1
TPM1	NM_001407337.1 link	c.803G>A	p.Arg268His	missense_variant	Exon 9 of 9	NP_001394266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TPM1	ENST00000317516.12 link	c.695G>A	p.Arg232His	missense_variant	Exon 8 of 8	1	ENSP00000322577.7	F5H7S3
TPM1	ENST00000334895.10 link	c.695G>A	p.Arg232His	missense_variant	Exon 8 of 8	1	ENSP00000334624.4	P09493-5
TPM1	ENST00000267996.11 link	c.773-1190G>A		intron_variant	Intron 8 of 8	1	ENSP00000267996.7	P09493-7

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000410

AC:

103

AN:

251390

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000174

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Feb 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg232His in exon 10A of TPM1: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (38/11578) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). -

Jul 28, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg232His variant in the TPM1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg232His occurs in an alternative transcript of TPM1, variant 6 (TMBr-3 brain isoform), which is reported to expressed in brain tissue in animal models (Lees-Miller et al., 1990; Stamm S et al., 1993). No mutations have been reported in this alternative transcript and it is unknown if this gene isoform is also expressed in the heart. Arg232His results in a conservative substitution of one positively charged amino acid for another at a residue that is not conserved across species. As a result, in silico analysis predicts Arg232His likely has a benign effect onthe protein structure/function. However, the NHLBI ESP Exome Variant Server reports Arg232His was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if the Arg232His variant in the TPM1 is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -

Mar 05, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.Arg232His (R232H; c.695 G>A) in the TPM1 gene This is a completely novel variant. The testing lab reports that Arg232His occurs in an alternative transcript of TPM1 (TMBr-3 brain isoform), which is expressed in brain tissue in animal models (Lees-Miller et al. 1990, Stamm et al. 1993). No disease-causing mutations have been reported in this alternative transcript (Stenson et al. 2009, the Human Gene Mutation Database) and it is unknown if this gene isoform is also expressed in the heart. This is a conservative amino acid change, resulting in the replacement of a basic, positively-charged arginine with a basic, positively-charged histidine. GeneDx reports that the arginine at this location is not conserved across species and that in silico analysis predicts the change to be benign. This is not a common polymorphism. In total the variant has not been seen in >6500 individuals from publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however, as our patient is of Mexican ancestry. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of December 2, 2012). No variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). It is not found in 1000 genomes (http://browser.1000genomes.org/index.htm), which contained 70 individuals of Mexican ancestry from Los Angeles, as of May 13, 2012. -

Cardiomyopathy

Benign:1

Dec 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Pathogenic

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.019

T;T

MetaSVM

Pathogenic

1.1

PROVEAN

Benign

-0.31

N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.056

T;T

Vest4

0.24

MVP

0.67

ClinPred

0.20

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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