Genetic Variant ENST00000558314.5:n.3_34delACTCCCGCTCCTCCGCCCGACCGCGCGCTCGC (chr15-63042743-CCGCGCTCGCACTCCCGCTCCTCCGCCCGACCG-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000558314.5(TPM1):n.3_34delACTCCCGCTCCTCCGCCCGACCGCGCGCTCGC variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000113 in 1,064,000 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TPM1
ENST00000558314.5 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02

Publications

0 publications found

Variant links:

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 links:

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

TPM1-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.-86_-55delCGCGCTCGCACTCCCGCTCCTCCGCCCGACCG	5_prime_UTR_variant	Exon 1 of 10	ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4
TPM1	NM_001018005.2 link	c.-86_-55delCGCGCTCGCACTCCCGCTCCTCCGCCCGACCG	non_coding_transcript_variant		ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4
TPM1	NM_001018005.2 link	c.-86_-55delCGCGCTCGCACTCCCGCTCCTCCGCCCGACCG	upstream_gene_variant		ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.-77_-46delACTCCCGCTCCTCCGCCCGACCGCGCGCTCGC		5_prime_UTR_variant	Exon 1 of 10	1	NM_001018005.2	ENSP00000385107.4		P09493-1
TPM1	ENST00000403994.9 link	c.-86_-55delCGCGCTCGCACTCCCGCTCCTCCGCCCGACCG		upstream_gene_variant		1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

911776

Hom.:

AF XY:

0.00000852

AC XY:

AN XY:

469386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22522

American (AMR)

AF:

0.00

AC:

AN:

34204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21132

East Asian (EAS)

AF:

0.00

AC:

AN:

34892

South Asian (SAS)

AF:

0.00

AC:

AN:

69906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3634

European-Non Finnish (NFE)

AF:

0.0000173

AC:

AN:

635010

Other (OTH)

AF:

0.00

AC:

AN:

41794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 02, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; No data available from ethnically-matched control populations to assess the frequency of this variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

Splicing

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

Publications

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ENST00000558314.5:n.3_34delACTCCCGCTCCTCCGCCCGACCGCGCGCTCGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over