rs397516373

Positions:

chr15-63059663-G-A

Variant summary

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

The ENST00000403994.9(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
ENST00000403994.9 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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000403994.9

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.475G>A	p.Asp159Asn	missense_variant	4/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.475G>A	p.Asp159Asn	missense_variant	4/10	1	NM_001018005.2	ENSP00000385107	A1	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Aug 21, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 11, 2011	- -

Familial cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 30, 2018

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

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 19, 2019

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 18, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43420). 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; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). 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). -

Dilated cardiomyopathy 1Y

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Baylor Genetics

Sep 01, 2017

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;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

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