rs1060501863

Variant summary

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

The NM_001018005.2(TPM1):​c.112C>G​(p.Gln38Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

TPM1
NM_001018005.2 missense, splice_region

Scores

2
9
9
Splicing: ADA: 0.9423
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.72
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]

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ACMG classification

Classification made for transcript

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 8 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). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. GenCC has associacion of the 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 Protein UniProt
TPM1NM_001018005.2 linkc.112C>G p.Gln38Glu missense_variant, splice_region_variant 1/10 ENST00000403994.9 NP_001018005.1 P09493-1D9YZV4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPM1ENST00000403994.9 linkc.112C>G p.Gln38Glu missense_variant, splice_region_variant 1/101 NM_001018005.2 ENSP00000385107.4 P09493-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 29, 2019This missense variant replaces glutamine with glutamic acid at codon 38 of the TPM1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein function. Computational splicing tools suggest that this variant may impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2025This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 38 of the TPM1 protein (p.Gln38Glu). This variant is not present in population databases (gnomAD no frequency). 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: 408132). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
CardioboostCm
Uncertain
0.77
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
.;.;T;.;T;T;.;.;.;.;.
Eigen
Benign
0.091
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.2
M;M;.;.;M;.;M;M;M;M;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.0
N;N;.;N;N;N;N;N;N;.;.
REVEL
Uncertain
0.46
Sift
Benign
0.047
D;D;.;D;D;D;T;D;D;.;.
Sift4G
Benign
0.24
T;T;T;T;T;T;T;T;T;.;.
Polyphen
0.0, 0.037
.;.;.;.;B;B;.;.;.;B;.
Vest4
0.53
MutPred
0.21
Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);Loss of MoRF binding (P = 0.264);
MVP
0.90
MPC
1.6
ClinPred
0.90
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.32
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.94
dbscSNV1_RF
Benign
0.62
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs1060501863; hg19: chr15-63335140; API