15-63042874-G-T

Position:

• chr15-63042874-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The ENST00000403994.9(TPM1):​c.45G>T​(p.Lys15Asn) 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. K15R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 ENST00000403994.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.78

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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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, 0.819
• PP5: Variant 15-63042874-G-T is Pathogenic according to our data. Variant chr15-63042874-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31892.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}. Variant chr15-63042874-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.45G>T	p.Lys15Asn	missense_variant	1/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.45G>T	p.Lys15Asn	missense_variant	1/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects TPM1 protein function (PMID: 28732641; 26873245). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 20215591, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31892). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 15 of the TPM1 protein (p.Lys15Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 01, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Lys15Asn va riant in TPM1 has been reported in 1 individual with DCM, was absent from 492 ra ce-matched control chromosomes (372 Caucasian) and segregated with disease in 2 other affected relatives (Hershberger 2010, Rampersaud 2011). In addition, this variant has been identified in 1 out of >3600 probands (>2200 Caucasian) tested by our laboratory and segregated with disease in 1 affected sibling (LMM unpubli shed data). The Lys15Asn variant has not been identified in large and broad popu lations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) ; this low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Lys 15Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the low frequency of this variant and segregation with disease suggest that it may be pathogenic, but additional information is needed to fully assess its clinical significance. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (TPM1)

Apr 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;T;.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;.;.;H;.;H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D;D;.;D;D;N;D;N;N;.;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;.;.
Sift4G	Uncertain	0.023	D;T;D;D;D;D;D;D;D;.;.
Polyphen		1.0, 1.0	.;.;.;.;D;D;.;.;.;D;.
Vest4		0.78
MutPred		0.33		Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);Loss of ubiquitination at K15 (P = 0.0081);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.93
gMVP		0.89

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: rs199476301; hg19: chr15-63335073;