rs11558747

Variant names:

• chr15-63059674-T-C
• rs11558747
• NM_001018005.2:c.486T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018005.2(TPM1):​c.486T>C​(p.Tyr162Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,607,220 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (246 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2839 hom.)
• Consequence: TPM1 NM_001018005.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 2.29
• Publications: 6 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-63059674-T-C is Benign according to our data. Variant chr15-63059674-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

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.486T>C	p.Tyr162Tyr	synonymous	Exon 4 of 10	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.612T>C	p.Tyr204Tyr	synonymous	Exon 5 of 10	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.612T>C	p.Tyr204Tyr	synonymous	Exon 5 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.486T>C	p.Tyr162Tyr	synonymous	Exon 4 of 10	ENSP00000385107.4	P09493-1
	TPM1	ENST00000267996.11	TSL:1	c.486T>C	p.Tyr162Tyr	synonymous	Exon 4 of 9	ENSP00000267996.7	P09493-7
	TPM1	ENST00000288398.10	TSL:1	c.486T>C	p.Tyr162Tyr	synonymous	Exon 4 of 10	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7428 AN: 152090 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0541 AC: 13604 AN: 251316 AF XY: 0.0548

Gnomad AFR exome AF: 0.00973

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.0715

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0580 AC: 84429 AN: 1455012 Hom.: 2839 Cov.: 30 AF XY: 0.0574 AC XY: 41563 AN XY: 724130

African (AFR) AF: 0.00996 AC: 332 AN: 33336

American (AMR) AF: 0.0356 AC: 1585 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2689 AN: 25982

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39352

South Asian (SAS) AF: 0.0208 AC: 1788 AN: 85984

European-Finnish (FIN) AF: 0.0984 AC: 5200 AN: 52836

Middle Eastern (MID) AF: 0.115 AC: 658 AN: 5734

European-Non Finnish (NFE) AF: 0.0621 AC: 68717 AN: 1107212

Other (OTH) AF: 0.0577 AC: 3459 AN: 59994

GnomAD4 genome AF: 0.0487 AC: 7419 AN: 152208 Hom.: 246 Cov.: 32 AF XY: 0.0496 AC XY: 3692 AN XY: 74430

African (AFR) AF: 0.0106 AC: 441 AN: 41524

American (AMR) AF: 0.0589 AC: 900 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.0983 AC: 1041 AN: 10586

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4429 AN: 67996

Other (OTH) AF: 0.0625 AC: 132 AN: 2112

Alfa AF: 0.0578 Hom.: 222

Bravo AF: 0.0445

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0733

EpiControl AF: 0.0745

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Cardiomyopathy (3)
-	-	3	Hypertrophic cardiomyopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1Y (1)
-	-	1	Hypertrophic cardiomyopathy 3 (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.87
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism (auto)

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: rs11558747; hg19: chr15-63351873; COSMIC: COSV51261387; COSMIC: COSV51261387;