rs397516385

Positions:

• chr15-63062267-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001018005.2(TPM1):​c.692A>G​(p.Lys231Arg) 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 61 pathogenic changes around while only 1 benign (98%) 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). 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.692A>G	p.Lys231Arg	missense_variant	7/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.692A>G	p.Lys231Arg	missense_variant	7/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2012

The Lys231Arg variant (TPM1) has not been reported in the literature but has bee n identified in one individual (this individual's father) by our laboratory. Co mputational analyses (biochemical amino acid properties, conservation, PolyPhen2 , SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In the absence of additional information, the clinical significance of this vari ant cannot be determined. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;L;L;.;L;L;L;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;.;.;N;N;.;N;N;N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.058	T;D;T;D;D;D;D;.;.;D;T;.;D;D;D;D
Sift4G	Benign	0.49	T;T;T;T;T;T;T;.;.;T;T;.;T;T;T;T
Polyphen		0.91, 0.48, 0.38, 0.044	.;.;P;P;.;.;.;B;.;.;.;.;.;B;.;.
Vest4		0.72
MutPred		0.57		.;.;.;Loss of ubiquitination at K273 (P = 0.0059);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		2.3
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516385; hg19: chr15-63354466;