NM_001018005.2:c.23T>G

Variant names:

• chr15-63042852-T-G
• rs397516364
• NM_001018005.2:c.23T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001018005.2(TPM1):​c.23T>G​(p.Met8Arg) 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. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M8T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.72
• Publications: 7 publications found

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]

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 15-63042852-T-G is Pathogenic according to our data. Variant chr15-63042852-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 43406.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.23T>G	p.Met8Arg	missense_variant	Exon 1 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.23T>G	p.Met8Arg	missense_variant	Exon 1 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Mar 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;.;D;.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;H;.;H;H;H;H;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D;.;D;D;D;D;D;D;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;T;D;D;.;.
Polyphen		1.0, 1.0	.;.;.;.;D;D;.;.;.;D;.
Vest4		0.94
MutPred		0.33		Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);Loss of ubiquitination at K12 (P = 0.0286);
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.061	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516364; hg19: chr15-63335051;