rs104894501

Positions:

• chr15-63044030-G-A
• chr15-63044030-G-C
• chr15-63044030-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The ENST00000403994.9(TPM1):​c.118G>A​(p.Glu40Lys) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E40Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 ENST00000403994.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 129 pathogenic changes around while only 5 benign (96%) 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, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.118G>A	p.Glu40Lys	missense_variant	2/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.118G>A	p.Glu40Lys	missense_variant	2/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1Y Pathogenic:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2022

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. Experimental studies have shown that this missense change affects TPM1 function (PMID: 15923195, 19222994, 21741356, 23539503, 32618513). 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: 12459). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 11273725). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 40 of the TPM1 protein (p.Glu40Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;D;T;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;H;.;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PROVEAN	Uncertain	-2.5	N;N;.;D;N;N;D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.015	D;D;D;D;D;T;T;.
Polyphen		0.92, 0.70	.;.;.;.;P;P;.;.
Vest4		0.82
MutPred		0.27		.;.;.;.;.;Gain of ubiquitination at E82 (P = 0.0037);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs104894501; hg19: chr15-63336229; COSMIC: COSV51263903; COSMIC: COSV51263903;