NM_001018005.2:c.184G>C

Variant names:

• chr15-63044096-G-C
• rs199476305
• NM_001018005.2:c.184G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001018005.2(TPM1):​c.184G>C​(p.Glu62Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E62G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.56
• Publications: 19 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 15-63044096-G-C is Pathogenic according to our data. Variant chr15-63044096-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 31876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018005.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.184G>C	p.Glu62Gln	missense	Exon 2 of 10	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.310G>C	p.Glu104Gln	missense	Exon 3 of 10	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.310G>C	p.Glu104Gln	missense	Exon 3 of 11	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000403994.9	TSL:1 MANE Select	c.184G>C	p.Glu62Gln	missense	Exon 2 of 10	ENSP00000385107.4	P09493-1
	TPM1	ENST00000288398.10	TSL:1	c.184G>C	p.Glu62Gln	missense	Exon 2 of 10	ENSP00000288398.6	P09493-10
	TPM1	ENST00000358278.7	TSL:1	c.184G>C	p.Glu62Gln	missense	Exon 2 of 9	ENSP00000351022.3	P09493-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.16	T
Polyphen		0.82	P
Vest4		0.78
MutPred		0.62		Gain of methylation at K107 (P = 0.1459)
MVP		0.98
MPC		2.3
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199476305; hg19: chr15-63336295;