rs886051319

Variant names:

• chr15-63042716-G-A
• rs886051319
• ENST00000288398.10:c.-114G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000288398.10(TPM1):​c.-114G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000551 in 816,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: TPM1 ENST00000288398.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.03
• Publications: 1 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-AS (HGNC:53635): (TPM1 antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000288398.10. 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.-114G>A		upstream_gene	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.-114G>A		upstream_gene	N/A	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.-114G>A		upstream_gene	N/A	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000288398.10	TSL:1	c.-114G>A		5_prime_UTR	Exon 1 of 10	ENSP00000288398.6	P09493-10
	TPM1	ENST00000358278.7	TSL:1	c.-114G>A		5_prime_UTR	Exon 1 of 9	ENSP00000351022.3	P09493-3
	TPM1	ENST00000893959.1		c.-114G>A		5_prime_UTR	Exon 1 of 10	ENSP00000564018.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 40 AN: 664728 Hom.: 0 Cov.: 9 AF XY: 0.0000653 AC XY: 23 AN XY: 352064

African (AFR) AF: 0.00 AC: 0 AN: 17342

American (AMR) AF: 0.00 AC: 0 AN: 31140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18586

East Asian (EAS) AF: 0.00 AC: 0 AN: 32826

South Asian (SAS) AF: 0.00 AC: 0 AN: 61050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2806

European-Non Finnish (NFE) AF: 0.0000952 AC: 40 AN: 420218

Other (OTH) AF: 0.00 AC: 0 AN: 33530

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1Y (1)
-	1	-	Hypertrophic cardiomyopathy 3 (1)
-	1	-	Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.97
PhyloP100		4.0
PromoterAI		-0.35	Neutral

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: rs886051319; hg19: chr15-63334915; COSMIC: COSV51266082; COSMIC: COSV51266082;