15-63042499-C-G

Variant names:

• chr15-63042499-C-G
• rs8042834
• NM_001018005.2:c.-331C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001018005.2(TPM1):​c.-331C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 260,302 control chromosomes in the GnomAD database, including 3,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1524 hom., cov: 32)
  • Exomes 𝑓: 0.14 (1623 hom.)
• Consequence: TPM1 NM_001018005.2 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0960

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-63042499-C-G is Benign according to our data. Variant chr15-63042499-C-G is described in ClinVar as [Benign]. Clinvar id is 668730.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.-331C>G		upstream_gene_variant		ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.-331C>G		upstream_gene_variant		1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18602 AN: 151978 Hom.: 1515 Cov.: 32

Gnomad AFR AF: 0.0857

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.144 AC: 15564 AN: 108212 Hom.: 1623 AF XY: 0.160 AC XY: 9465 AN XY: 59220

Gnomad4 AFR exome AF: 0.0627

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0822

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.122 AC: 18628 AN: 152090 Hom.: 1524 Cov.: 32 AF XY: 0.129 AC XY: 9609 AN XY: 74344

Gnomad4 AFR AF: 0.0856

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0796

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0543 Hom.: 52

Bravo AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.7
DANN	Benign	0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8042834; hg19: chr15-63334698;