chr15-63042927-A-C

Position:

• chr15-63042927-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001018005.2(TPM1):​c.98A>C​(p.Glu33Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E33K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.10

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Disordered (size 37) in uniprot entity TPM1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001018005.2
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.98A>C	p.Glu33Ala	missense_variant	1/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.98A>C	p.Glu33Ala	missense_variant	1/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2021

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 265279; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

This sequence change in TPM1 is predicted to replace glutamic acid with alanine at codon 33, p.(Glu33Ala). The glutamic acid residue is highly conserved (94/94 vertebrates, UCSC), and is located in the coiled-coiled domain. There is a large physicochemical difference between glutamic acid and alanine. TPM1, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1 missense constraint score = 0.37). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been detected in at least two probands with a phenotype consistent with TPM1-related cardiac conditions (Royal Melbourne Hospital; Invitae). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.703). Another missense variant c.97G>A, p.(Glu33Lys) in the same codon has been reported in individuals with dilated cardiomyopathy (PMID: 24503780, 30847666, 30923642). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS4_Supporting, PM2_Supporting, PP2, PP3. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2017

This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 265279). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 33 of the TPM1 protein (p.Glu33Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;D;.;D;T;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;M;.;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D;N;D;D;D;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;.;D;D;D;D;D;D;.;.
Sift4G	Uncertain	0.044	D;D;D;D;D;D;D;D;D;.;.
Polyphen		0.81, 0.99, 0.88	.;.;.;.;P;D;.;.;.;P;.
Vest4		0.78
MutPred		0.23		Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);Gain of MoRF binding (P = 0.1739);
MVP		0.92
MPC		2.5
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.93

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: rs886039444; hg19: chr15-63335126;