rs730881159

chr15-63061774-G-Achr15-63061774-G-Cchr15-63061774-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001018005.2(TPM1):c.625G>A(p.Ala209Thr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A209S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0

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 8 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, 6 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TPM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 15-63061774-G-A is Pathogenic according to our data. Variant chr15-63061774-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181686.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.625G>A	p.Ala209Thr	missense_variant	6/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.625G>A	p.Ala209Thr	missense_variant	6/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2014

The A209T variant is likely pathogenic and was identified in the TPM1 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A209T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A209T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (T201M, Q210R, A211G, S215L) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 08, 2023

This missense variant replaces alanine with threonine at codon 209 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TPM1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Uncertain	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.;.;.;.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;H;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-2.8	D;D;D;D;.;.;D;.;D
REVEL	Pathogenic	0.70
Sift	Benign	0.035	D;D;D;D;.;.;D;.;D
Sift4G	Benign	0.18	T;T;T;T;.;.;T;.;T
Polyphen		0.96	D;P;.;.;P;.;.;.;.
Vest4		0.80
MutPred		0.43		.;Gain of phosphorylation at A251 (P = 0.118);.;.;.;.;.;.;.;
MVP		0.96
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34

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: rs730881159; hg19: chr15-63353973;