chr15-63042436-C-G

Variant names:

• chr15-63042436-C-G
• rs3825973
• ENST00000288398.10:c.-394C>G

Variant summary

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

The ENST00000288398.10(TPM1):​c.-394C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 151,922 control chromosomes in the GnomAD database, including 1,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1492 hom., cov: 33)
• Consequence: TPM1 ENST00000288398.10 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.675

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=-0.81).
• BP6: Variant 15-63042436-C-G is Benign according to our data. Variant chr15-63042436-C-G is described in ClinVar as [Benign]. Clinvar id is 668729.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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000288398.10	c.-394C>G		upstream_gene_variant		1		ENSP00000288398.6
TPM1	ENST00000358278.7	c.-394C>G		upstream_gene_variant		1		ENSP00000351022.3
TPM1	ENST00000559831.6	n.-394C>G		upstream_gene_variant		5		ENSP00000452977.2

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18260 AN: 151808 Hom.: 1483 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0621

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.114

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

GnomAD4 genome AF: 0.120 AC: 18287 AN: 151922 Hom.: 1492 Cov.: 33 AF XY: 0.127 AC XY: 9467 AN XY: 74286

Gnomad4 AFR AF: 0.0784

Gnomad4 AMR AF: 0.112

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: 0.120

Alfa AF: 0.0608 Hom.: 58

Bravo AF: 0.116

Asia WGS AF: 0.370 AC: 1280 AN: 3470

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	-0.81
CADD	Benign	3.2
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3825973; hg19: chr15-63334635;