15-63060887-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_001018005.2(TPM1):c.511A>G(p.Ile171Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.32

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

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: 3.9402 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.511A>G	p.Ile171Val	missense_variant	Exon 5 of 10	ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.511A>G	p.Ile171Val	missense_variant	Exon 5 of 10	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y

Uncertain:1

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 171 of the TPM1 protein (p.Ile171Val). This variant is present in population databases (rs774903903, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1430748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Nov 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I171V variant (also known as c.511A>G), located in coding exon 5 of the TPM1 gene, results from an A to G substitution at nucleotide position 511. The isoleucine at codon 171 is replaced by valine, an amino acid with highly similar properties. This variant was observed in one control individual from a hypertrophic cardiomyopathy (HCM) study; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.035

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;.;D;D;.;.;.;.;.;.;D;.;.;.;D;D

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.6

L;L;L;.;L;L;L;L;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.65

N;N;N;N;N;N;N;.;.;N;N;.;N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.093

T;T;T;T;T;T;T;.;.;T;T;.;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T;T;T;.;.;T;T;.;T;T;T;T

Polyphen

0.0020, 0.0, 0.0040

.;.;B;B;.;.;.;B;.;.;.;.;.;B;.;.

Vest4

0.60

MutPred

0.53

.;.;.;Loss of catalytic residue at L218 (P = 0.0541);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.90

MPC

1.2

ClinPred

0.40

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.70

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