chr15-63048609-A-T

Variant names:

Variant summary

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

The ENST00000404484.9(TPM1):c.34A>T(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,533,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TPM1
ENST00000404484.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

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 GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.240+4457A>T		intron_variant	Intron 2 of 9	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.240+4457A>T		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1381306

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681332

show subpopulations

African (AFR)

AF:

0.0000342

AC:

AN:

29240

American (AMR)

AF:

0.00

AC:

AN:

34964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24590

East Asian (EAS)

AF:

0.00

AC:

AN:

34350

South Asian (SAS)

AF:

0.00

AC:

AN:

78224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073938

Other (OTH)

AF:

0.0000174

AC:

AN:

57396

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

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 28, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg12Trp variant in TPM1 has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. At this time, additional information is need ed to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

.;D;.;.;.;D

Eigen

Benign

0.13

Eigen_PC

Benign

-0.098

FATHMM_MKL

Benign

0.50

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.61

D;D;D;D;D;D

MetaSVM

Uncertain

0.55

PhyloP100

1.1

PROVEAN

Uncertain

-4.2

D;D;.;D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;.;D;D;D

Polyphen

1.0, 0.99

.;.;.;D;D;.

Vest4

0.42

MutPred

0.51

Gain of ubiquitination at K13 (P = 0.0745);Gain of ubiquitination at K13 (P = 0.0745);Gain of ubiquitination at K13 (P = 0.0745);Gain of ubiquitination at K13 (P = 0.0745);Gain of ubiquitination at K13 (P = 0.0745);Gain of ubiquitination at K13 (P = 0.0745);

MVP

0.80

ClinPred

0.51

GERP RS

0.12

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=76/24

polymorphism

(source)

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

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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