rs397516490

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The ENST00000404484.9(TPM1):c.7G>A(p.Gly3Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,528,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G3G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TPM1
ENST00000404484.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.84

Publications

2 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: Benign. The variant received -9 ACMG points.

BP6

Variant 15-63048582-G-A is Benign according to our data. Variant chr15-63048582-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43683.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000371 (51/1376170) while in subpopulation MID AF = 0.00208 (10/4808). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.240+4430G>A		intron_variant	Intron 2 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.240+4430G>A		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000719

AC:

AN:

125154

AF XY:

0.0000583

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.000214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000425

Gnomad OTH exome

AF:

0.000266

GnomAD4 exome

AF:

0.0000371

AC:

AN:

1376170

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

678786

show subpopulations

African (AFR)

AF:

0.0000347

AC:

AN:

28838

American (AMR)

AF:

0.000201

AC:

AN:

34792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24554

East Asian (EAS)

AF:

0.00

AC:

AN:

34078

South Asian (SAS)

AF:

0.00

AC:

AN:

77972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41008

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

4808

European-Non Finnish (NFE)

AF:

0.0000233

AC:

AN:

1072884

Other (OTH)

AF:

0.000140

AC:

AN:

57236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000460

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000117

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000149

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Long QT syndrome;C0340493:Paroxysmal familial ventricular fibrillation

Benign:1

Nov 21, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The TPM1 Gly3Arg variant has been identified previously in 1 (heterozygous) proband with left ventricular dilation, wall thinning (LMM, Pers. Comm). It has also been identified in 1 Saudi Arabian family with 2 children affected with DCM and 1 child affected with Patent Ductus Arteruisus, all 3 children were found to be homozygous for p.Gly3Arg, the heterozygous parents were not affected (Al Harbi K, et al., 2016). We identified this variant in 2 heterozygous probands, The first was diagnosed with Long QT. The second was diagnosed with idiopathic ventricular fibrillation, and has a family history of sudden death. The variant is found in Genome Aggregation Database (MAF=0.00007917, http://gnomad.broadinstitute.org/), and the Greater Middle Eastern variome project (MAF= 0.00304, http://igm.ucsd.edu/gme/) which is higher then expected for a genetic heart condition. In silico tools PolyPhen-2 and MutationTaster predict this variant to be benign, however SIFT predicts this variant to be "deleterious". In summary, the variant is unlikely to be causing disease as it is present in the general population at an elevated frequency, evidence suggests it may only cause disease when inherited in the homozygous form, furthermore the variant has not been identified in consistent phenotypes and 2/3 in silico tools predict the variant to be benign, therefore we classify TPM1 Gly3Arg as 'likely benign'. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T;.;.;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.55

D;D;D;D;D;D

MetaSVM

Uncertain

0.42

PhyloP100

5.8

PROVEAN

Benign

-1.6

N;N;.;N;N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D;.;D;D;D

Sift4G

Uncertain

0.041

D;D;.;D;D;D

Polyphen

0.99, 0.97

.;.;.;D;D;.

Vest4

0.19

MutPred

0.21

Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);

MVP

0.38

ClinPred

0.63

GERP RS

3.8

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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