15-63051119-T-C

Variant names:

• chr15-63051119-T-C
• rs3803499
• NM_001018005.2:c.241-5866T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001018005.2(TPM1):​c.241-5866T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,084 control chromosomes in the GnomAD database, including 7,897 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7897 hom., cov: 33)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.572
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 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.241-5866T>C		intron	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.367-5866T>C		intron	N/A	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.367-5866T>C		intron	N/A	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000403994.9	TSL:1 MANE Select	c.241-5866T>C		intron	N/A	ENSP00000385107.4	P09493-1
	TPM1	ENST00000267996.11	TSL:1	c.241-5866T>C		intron	N/A	ENSP00000267996.7	P09493-7
	TPM1	ENST00000288398.10	TSL:1	c.241-5866T>C		intron	N/A	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46124 AN: 151966 Hom.: 7879 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.304 AC: 46177 AN: 152084 Hom.: 7897 Cov.: 33 AF XY: 0.305 AC XY: 22695 AN XY: 74336

African (AFR) AF: 0.478 AC: 19834 AN: 41482

American (AMR) AF: 0.316 AC: 4832 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3470

East Asian (EAS) AF: 0.183 AC: 945 AN: 5170

South Asian (SAS) AF: 0.243 AC: 1170 AN: 4824

European-Finnish (FIN) AF: 0.263 AC: 2770 AN: 10532

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14671 AN: 67998

Other (OTH) AF: 0.295 AC: 622 AN: 2112

Alfa AF: 0.159 Hom.: 406

Bravo AF: 0.320

Asia WGS AF: 0.204 AC: 713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.0
DANN	Benign	0.83
PhyloP100		0.57
Mutation Taster		=100/0	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: rs3803499; hg19: chr15-63343318;