rs397516369

Variant names:

• chr15-63057081-C-G
• rs397516369
• NM_001018005.2:c.337C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-63057081-C-G
• chr15-63057081-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001018005.2(TPM1):​c.337C>G​(p.Leu113Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene TPM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.13
• Publications: 4 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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for TPM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 15-63057081-C-G is Pathogenic according to our data. Variant chr15-63057081-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43414.

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.337C>G	p.Leu113Val	missense	Exon 3 of 10	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.463C>G	p.Leu155Val	missense	Exon 4 of 10	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.463C>G	p.Leu155Val	missense	Exon 4 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.337C>G	p.Leu113Val	missense	Exon 3 of 10	ENSP00000385107.4	P09493-1
	TPM1	ENST00000267996.11	TSL:1	c.337C>G	p.Leu113Val	missense	Exon 3 of 9	ENSP00000267996.7	P09493-7
	TPM1	ENST00000288398.10	TSL:1	c.337C>G	p.Leu113Val	missense	Exon 3 of 10	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
1	-	-	Left ventricular noncompaction 9 (1)
1	-	-	not provided (1)
1	-	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.040	D
Polyphen		0.83	P
Vest4		0.76
MutPred		0.65		Gain of methylation at K154 (P = 0.0335)
MVP		0.93
MPC		2.5
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.99
Mutation Taster		=8/92	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: rs397516369; hg19: chr15-63349280;