rs11558748

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000267996.11(TPM1):c.*31G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

TPM1
ENST00000267996.11 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0320

Publications

13 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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
dilated cardiomyopathy 1Y
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TPM1 links:

ENSG00000259627 (HGNC:):

ENSG00000259627 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 15-63071203-G-A is Benign according to our data. Variant chr15-63071203-G-A is described in ClinVar as Benign. ClinVar VariationId is 257060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
TPM1	NR_176337.1 link	n.1045G>A	non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176338.1 link	n.2265G>A	non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176340.1 link	n.1064G>A	non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
TPM1	ENST00000267996.11 link	c.*31G>A	3_prime_UTR_variant	Exon 9 of 9	1	ENSP00000267996.7
TPM1	ENST00000358278.7 link	c.*31G>A	3_prime_UTR_variant	Exon 9 of 9	1	ENSP00000351022.3
TPM1	ENST00000404484.9 link	c.*31G>A	3_prime_UTR_variant	Exon 8 of 8	1	ENSP00000384315.4

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

AN:

8726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.250

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00657

AC:

AN:

10502

AF XY:

0.00501

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00309

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.00478

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00741

GnomAD4 exome

AF:

0.000827

AC:

188

AN:

227210

Hom.:

Cov.:

AF XY:

0.000782

AC XY:

AN XY:

116424

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00161

AC:

AN:

6210

American (AMR)

AF:

0.00

AC:

AN:

6522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4952

East Asian (EAS)

AF:

0.00319

AC:

AN:

2510

South Asian (SAS)

AF:

0.00129

AC:

AN:

18638

European-Finnish (FIN)

AF:

0.000437

AC:

AN:

11446

Middle Eastern (MID)

AF:

0.00304

AC:

AN:

988

European-Non Finnish (NFE)

AF:

0.000764

AC:

127

AN:

166324

Other (OTH)

AF:

0.00114

AC:

AN:

9620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00263

AC:

AN:

8736

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

AN XY:

4168

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

4006

American (AMR)

AF:

0.00407

AC:

AN:

492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

218

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00259

AC:

AN:

3092

Other (OTH)

AF:

0.00

AC:

AN:

120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00758

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

(source)

DANN

Benign

0.58

PhyloP100

0.032

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over