15-63042938-A-G

Variant summary

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

The NM_001018005.2(TPM1):​c.109A>G​(p.Lys37Glu) 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TPM1
NM_001018005.2 missense

Scores

3
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 7.28
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 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPM1NM_001018005.2 linkc.109A>G p.Lys37Glu missense_variant Exon 1 of 10 ENST00000403994.9 NP_001018005.1 P09493-1D9YZV4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPM1ENST00000403994.9 linkc.109A>G p.Lys37Glu missense_variant Exon 1 of 10 1 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:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1
Jul 26, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces lysine with glutamic acid at codon 37 of the TPM1 protein (p.Lys37Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with left ventricular noncompaction cardiomyopathy (PMID: 20965760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31897). 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. -

not provided Other:1
Apr 15, 2012
Leiden Muscular Dystrophy (TPM1)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
CardioboostCm
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
.;.;T;.;T;T;.;.;.;.;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.053
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.95
D;D;D;.;D;D;D;T;T;T;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
1.5
L;L;.;.;L;.;L;L;L;L;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.85
N;N;.;N;N;N;N;N;N;.;.
REVEL
Uncertain
0.54
Sift
Benign
0.22
T;D;.;T;T;D;D;D;D;.;.
Sift4G
Benign
0.40
T;T;T;T;T;T;T;T;T;.;.
Polyphen
0.0010, 0.99, 0.025
.;.;.;.;B;D;.;.;.;B;.
Vest4
0.69
MutPred
0.19
Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);Loss of ubiquitination at K37 (P = 0.0027);
MVP
0.97
MPC
2.8
ClinPred
0.96
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.47
gMVP
0.83

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.

Other links and lift over

dbSNP: rs199476303; hg19: chr15-63335137; API