15-63042644-G-A

Position:

• chr15-63042644-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000288398.10(TPM1):​c.-186G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 561,006 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (10 hom.)
• Consequence: TPM1 ENST00000288398.10 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.43

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-63042644-G-A is Benign according to our data. Variant chr15-63042644-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 316682.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152316) while in subpopulation SAS AF= 0.00724 (35/4832). AF 95% confidence interval is 0.00535. There are 1 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000288398.10	c.-186G>A		5_prime_UTR_variant	1/10	1		ENSP00000288398	A1
TPM1	ENST00000559831.6	c.-186G>A		5_prime_UTR_variant, NMD_transcript_variant	1/10	5		ENSP00000452977
TPM1	ENST00000358278.7			upstream_gene_variant		1		ENSP00000351022

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00197 AC: 804 AN: 408690 Hom.: 10 Cov.: 4 AF XY: 0.00251 AC XY: 546 AN XY: 217932

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000942

Gnomad4 ASJ exome AF: 0.00503

Gnomad4 EAS exome AF: 0.0000373

Gnomad4 SAS exome AF: 0.00793

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.000805 AC XY: 60 AN XY: 74490

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.00101

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TPM1: BS1 -

Hypertrophic cardiomyopathy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dilated cardiomyopathy 1Y Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs541046450; hg19: chr15-63334843;