rs397516490

Positions:

chr15-63048582-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id is 43683.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.240+4430G>A		intron_variant		ENST00000403994.9	NP_001018005.1
TPM1-AS	NR_147233.2 linkuse as main transcript	n.661C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.240+4430G>A		intron_variant		1	NM_001018005.2	ENSP00000385107	A1	P09493-1
TPM1-AS	ENST00000561241.1 linkuse as main transcript	n.806C>T		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.0000719

AC:

AN:

125154

Hom.:

AF XY:

0.0000583

AC XY:

AN XY:

68656

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000347

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000233

Gnomad4 OTH exome

AF:

0.000140

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 14, 2014

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

Ventricular fibrillation;C0151878:Prolonged QT interval

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Nov 21, 2017

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

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

0.090

CADD

Benign

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;N;N;N;N;N

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over