rs1071646

Variant names:

• chr15-63059641-C-A
• rs1071646
• NM_001018005.2:c.453C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63059641-C-A
• chr15-63059641-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001018005.2(TPM1):​c.453C>A​(p.Ala151Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,610,730 control chromosomes in the GnomAD database, including 357,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32801 hom., cov: 31)
  • Exomes 𝑓: 0.66 (324998 hom.)
• Consequence: TPM1 NM_001018005.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 3.42
• Publications: 41 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-63059641-C-A is Benign according to our data. Variant chr15-63059641-C-A is described in ClinVar as Benign. ClinVar VariationId is 31888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 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.453C>A	p.Ala151Ala	synonymous	Exon 4 of 10	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.579C>A	p.Ala193Ala	synonymous	Exon 5 of 10	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.579C>A	p.Ala193Ala	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.453C>A	p.Ala151Ala	synonymous	Exon 4 of 10	ENSP00000385107.4	P09493-1
	TPM1	ENST00000267996.11	TSL:1	c.453C>A	p.Ala151Ala	synonymous	Exon 4 of 9	ENSP00000267996.7	P09493-7
	TPM1	ENST00000288398.10	TSL:1	c.453C>A	p.Ala151Ala	synonymous	Exon 4 of 10	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99022 AN: 151884 Hom.: 32785 Cov.: 31

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.636

GnomAD2 exomes AF: 0.670 AC: 168498 AN: 251338 AF XY: 0.674

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.555

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.958

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.652

Gnomad OTH exome AF: 0.674

GnomAD4 exome AF: 0.665 AC: 969963 AN: 1458728 Hom.: 324998 Cov.: 44 AF XY: 0.666 AC XY: 483250 AN XY: 725788

African (AFR) AF: 0.616 AC: 20548 AN: 33376

American (AMR) AF: 0.563 AC: 25111 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 17308 AN: 26038

East Asian (EAS) AF: 0.952 AC: 37679 AN: 39584

South Asian (SAS) AF: 0.702 AC: 60507 AN: 86132

European-Finnish (FIN) AF: 0.698 AC: 37086 AN: 53108

Middle Eastern (MID) AF: 0.596 AC: 3434 AN: 5762

European-Non Finnish (NFE) AF: 0.656 AC: 727733 AN: 1109902

Other (OTH) AF: 0.674 AC: 40557 AN: 60194

GnomAD4 genome AF: 0.652 AC: 99072 AN: 152002 Hom.: 32801 Cov.: 31 AF XY: 0.656 AC XY: 48748 AN XY: 74284

African (AFR) AF: 0.613 AC: 25365 AN: 41410

American (AMR) AF: 0.577 AC: 8803 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2267 AN: 3472

East Asian (EAS) AF: 0.950 AC: 4917 AN: 5178

South Asian (SAS) AF: 0.724 AC: 3492 AN: 4826

European-Finnish (FIN) AF: 0.698 AC: 7371 AN: 10556

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.657 AC: 44653 AN: 67978

Other (OTH) AF: 0.639 AC: 1348 AN: 2108

Alfa AF: 0.657 Hom.: 150650

Bravo AF: 0.646

Asia WGS AF: 0.818 AC: 2845 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.644

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	-	2	Dilated cardiomyopathy 1Y (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy 3 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	not provided (2)
-	-	1	TPM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		3.4
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: rs1071646; hg19: chr15-63351840; COSMIC: COSV51261240; COSMIC: COSV51261240;