ENST00000560903.1:n.1076C>T

Variant names:

• chr15-63048028-G-A
• rs4075583
• ENST00000560903.1:n.1076C>T

Variant summary

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

The ENST00000560903.1(TPM1-AS):​n.1076C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 309,072 control chromosomes in the GnomAD database, including 54,716 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 0.58 (26314 hom., cov: 33)
  • Exomes 𝑓: 0.59 (28402 hom.)
• Consequence: TPM1-AS ENST00000560903.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 23 publications found

Genes affected

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.240+3876G>A		intron_variant	Intron 2 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.240+3876G>A		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88578 AN: 151976 Hom.: 26297 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.599

GnomAD4 exome AF: 0.592 AC: 92887 AN: 156976 Hom.: 28402 Cov.: 0 AF XY: 0.570 AC XY: 50271 AN XY: 88180

African (AFR) AF: 0.530 AC: 724 AN: 1366

American (AMR) AF: 0.724 AC: 4389 AN: 6062

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2030 AN: 3288

East Asian (EAS) AF: 0.436 AC: 799 AN: 1834

South Asian (SAS) AF: 0.437 AC: 16537 AN: 37854

European-Finnish (FIN) AF: 0.587 AC: 4788 AN: 8152

Middle Eastern (MID) AF: 0.517 AC: 277 AN: 536

European-Non Finnish (NFE) AF: 0.651 AC: 58790 AN: 90316

Other (OTH) AF: 0.602 AC: 4553 AN: 7568

GnomAD4 genome AF: 0.583 AC: 88623 AN: 152096 Hom.: 26314 Cov.: 33 AF XY: 0.575 AC XY: 42799 AN XY: 74376

African (AFR) AF: 0.499 AC: 20702 AN: 41478

American (AMR) AF: 0.694 AC: 10613 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2160 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1858 AN: 5170

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4820

European-Finnish (FIN) AF: 0.561 AC: 5944 AN: 10594

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.640 AC: 43511 AN: 67950

Other (OTH) AF: 0.595 AC: 1256 AN: 2110

Alfa AF: 0.618 Hom.: 83251

Bravo AF: 0.591

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.73
PhyloP100		-0.014
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs4075583; hg19: chr15-63340227;