chr15-63042321-C-A

Variant names:

• chr15-63042321-C-A
• rs3809567
• ENST00000804116.1:n.122+6244G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000804116.1(TPM1-AS):​n.122+6244G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,230 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1521 hom., cov: 33)
• Consequence: TPM1-AS ENST00000804116.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0560
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 15-63042321-C-A is Benign according to our data. Variant chr15-63042321-C-A is described in ClinVar as Benign. ClinVar VariationId is 668727.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000804116.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1-AS	ENST00000804116.1		n.122+6244G>T		intron	N/A
	TPM1-AS	ENST00000804117.1		n.171+1067G>T		intron	N/A
	TPM1	ENST00000893958.1		c.-509C>A		upstream_gene	N/A	ENSP00000564017.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18576 AN: 152112 Hom.: 1512 Cov.: 33

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.116

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

GnomAD4 genome AF: 0.122 AC: 18608 AN: 152230 Hom.: 1521 Cov.: 33 AF XY: 0.129 AC XY: 9604 AN XY: 74430

African (AFR) AF: 0.0848 AC: 3522 AN: 41552

American (AMR) AF: 0.114 AC: 1747 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3470

East Asian (EAS) AF: 0.438 AC: 2256 AN: 5146

South Asian (SAS) AF: 0.306 AC: 1474 AN: 4822

European-Finnish (FIN) AF: 0.126 AC: 1341 AN: 10616

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.112 AC: 7638 AN: 68010

Other (OTH) AF: 0.122 AC: 257 AN: 2110

Alfa AF: 0.0624 Hom.: 59

Bravo AF: 0.119

Asia WGS AF: 0.374 AC: 1297 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.78
PhyloP100		0.056
PromoterAI		0.12	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3809567; hg19: chr15-63334520;