15-63048093-C-T

Variant names:

• chr15-63048093-C-T
• rs4075584
• ENST00000560903.1:n.1011G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000560903.1(TPM1-AS):​n.1011G>A 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 0.832 in 390,940 control chromosomes in the GnomAD database, including 135,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51934 hom., cov: 33)
  • Exomes 𝑓: 0.84 (83967 hom.)
• Consequence: TPM1-AS ENST00000560903.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-63048093-C-T is Benign according to our data. Variant chr15-63048093-C-T is described in ClinVar as Benign. ClinVar VariationId is 684019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000560903.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.240+3941C>T		intron	N/A	NP_001018005.1
	TPM1-AS	NR_147233.2		n.1150G>A		non_coding_transcript_exon	Exon 2 of 2
	TPM1	NM_001365778.1		c.366+3941C>T		intron	N/A	NP_001352707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1-AS	ENST00000560903.1	TSL:1	n.1011G>A		non_coding_transcript_exon	Exon 2 of 2
	TPM1	ENST00000403994.9	TSL:1 MANE Select	c.240+3941C>T		intron	N/A	ENSP00000385107.4
	TPM1	ENST00000267996.11	TSL:1	c.240+4262C>T		intron	N/A	ENSP00000267996.7

Frequencies

GnomAD3 genomes AF: 0.825 AC: 125448 AN: 152114 Hom.: 51874 Cov.: 33

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.816

GnomAD4 exome AF: 0.837 AC: 199884 AN: 238708 Hom.: 83967 Cov.: 0 AF XY: 0.840 AC XY: 114853 AN XY: 136754

African (AFR) AF: 0.808 AC: 3858 AN: 4776

American (AMR) AF: 0.910 AC: 15626 AN: 17178

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 5402 AN: 6866

East Asian (EAS) AF: 0.996 AC: 5628 AN: 5650

South Asian (SAS) AF: 0.871 AC: 44453 AN: 51054

European-Finnish (FIN) AF: 0.790 AC: 8131 AN: 10286

Middle Eastern (MID) AF: 0.705 AC: 612 AN: 868

European-Non Finnish (NFE) AF: 0.817 AC: 106979 AN: 130976

Other (OTH) AF: 0.832 AC: 9195 AN: 11054

GnomAD4 genome AF: 0.825 AC: 125567 AN: 152232 Hom.: 51934 Cov.: 33 AF XY: 0.826 AC XY: 61508 AN XY: 74422

African (AFR) AF: 0.810 AC: 33643 AN: 41538

American (AMR) AF: 0.882 AC: 13495 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2706 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5132 AN: 5160

South Asian (SAS) AF: 0.881 AC: 4255 AN: 4828

European-Finnish (FIN) AF: 0.786 AC: 8341 AN: 10612

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55389 AN: 67996

Other (OTH) AF: 0.818 AC: 1727 AN: 2112

Alfa AF: 0.825 Hom.: 24210

Bravo AF: 0.832

Asia WGS AF: 0.934 AC: 3246 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.72
DANN	Benign	0.92
PhyloP100		-1.8
PromoterAI		-0.0028	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: rs4075584; hg19: chr15-63340292;