rs727505043

chr15-63059646-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001018005.2(TPM1):c.458A>G(p.His153Arg) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H153D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 9 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, 5 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63059645-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43419.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, TPM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.458A>G	p.His153Arg	missense_variant	4/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.458A>G	p.His153Arg	missense_variant	4/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Sep 25, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The His153Arg v ariant in TPM1 has been identified by our laboratory in 1 neonate with HCM and p renatal cystic hygroma. Histidine (His) at position 153 is highly conserved in e volution and the change to arginine (Arg) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogen ic prediction is estimated to be correct 94% of the time (Jordan 2011). Although this data supports that the His153Arg variant may be pathogenic, additional stu dies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Sift4G	Benign	0.35	T;T;T;T;T;T;T;.;.;T;T;.;T;T;T;T
Polyphen		0.057, 0.17, 0.049, 0.82	.;.;B;B;.;.;.;B;.;.;.;.;.;P;.;.
Vest4		0.68
MutPred		0.64		.;.;.;Gain of MoRF binding (P = 0.0073);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.2
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.94

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: rs727505043; hg19: chr15-63351845;