rs397516373

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_001018005.2(TPM1):c.475G>A(p.Asp159Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 14 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

PP5

Variant 15-63059663-G-A is Pathogenic according to our data. Variant chr15-63059663-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63059663-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.475G>A	p.Asp159Asn	missense_variant	Exon 4 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.475G>A	p.Asp159Asn	missense_variant	Exon 4 of 10	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725268

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:2

Oct 11, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cardiomyopathy

Pathogenic:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tropomyosin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with cardiomyopathies (DCM, HCM and Ebstein anomaly of the tricuspid valve which can be associated with left ventricular non-compaction), including de novo reports (ClinVar, LOVD, PMID: 29517769, 27177193, 27532257). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy 3

Pathogenic:1

May 30, 2018

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiomyopathy

Pathogenic:1

Nov 19, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: TPM1 c.475G>A (p.Asp159Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251370 control chromosomes (gnomAD). c.475G>A has been reported in the literature in individuals affected with Cardiomyopathy, including two cases in which the mutation was identified as de-novo in children affected with Ebstein anomaly and left ventricular noncompaction (Kelle_2016) and dilated cardiomyopathy with left ventricular hypertophy (Herkert_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014) have cited the variant four times as pathogenic/likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was re-classified as pathogenic. -

Left ventricular noncompaction 9

Pathogenic:1

Jan 18, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jun 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available; This variant is associated with the following publications: (PMID: 29024827, 27532257, 28359939, 31737537, Kopylova 2021[poster], 27177193, 29517769) -

Hypertrophic cardiomyopathy

Pathogenic:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 159 of the TPM1 protein (p.Asp159Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardiomyopathy and Ebstein anomaly, left ventricular noncompaction cardiomyopathy (LVNC), and end-stage heart failure and hypertrophic cardiomyopathy (PMID: 27177193, 27532257; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43420). 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. For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1Y

Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was found once in our laboratory de novo in a 1-year-old female with left ventricular noncompaction, hypotonia, failure to thrive, developmental delay, and microcephaly. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T;D;T;T;T;T;D;D;T;T;D;T;T;D;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.81

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

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.9

H;H;H;.;H;H;H;H;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.6

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.062

T;T;T;T;T;T;T;.;.;T;T;.;T;D;T;D

Polyphen

0.87, 0.96, 1.0, 0.51

.;.;P;D;.;.;.;D;.;.;.;.;.;P;.;.

Vest4

0.89

MutPred

0.68

.;.;.;Gain of MoRF binding (P = 0.03);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

5.0

Varity_R

0.92

gMVP

0.96

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