rs62000429

Positions:

chr1-154191927-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_152263.4(TPM3):c.92A>C(p.Lys31Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,868 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 12 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 6 hom. )

Consequence

TPM3
NM_152263.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

TPM3 (HGNC:12012): (tropomyosin 3) This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

TPM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a coiled_coil_region (size 284) in uniprot entity TPM3_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) in NM_152263.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM3. . Gene score misZ 2.3546 (greater than the threshold 3.09). Trascript score misZ 3.2484 (greater than threshold 3.09). GenCC has associacion of gene with congenital generalized hypercontractile muscle stiffness syndrome, intermediate nemaline myopathy, congenital myopathy 4B, autosomal recessive, cap myopathy, congenital fiber-type disproportion myopathy, congenital myopathy 4A, autosomal dominant, TPM3-related myopathy, childhood-onset nemaline myopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.008729011).

BP6

Variant 1-154191927-T-G is Benign according to our data. Variant chr1-154191927-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 212413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154191927-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00547 (833/152336) while in subpopulation AFR AF= 0.0194 (805/41562). AF 95% confidence interval is 0.0183. There are 12 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM3	NM_152263.4 linkuse as main transcript	c.92A>C	p.Lys31Thr	missense_variant	1/10	ENST00000651641.1	NP_689476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1 linkuse as main transcript	c.92A>C	p.Lys31Thr	missense_variant	1/10		NM_152263.4	ENSP00000498577	P1	P06753-1

Frequencies

GnomAD3 genomes

AF:

0.00546

AC:

831

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.0000588

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00132

AC:

330

AN:

249372

Hom.:

AF XY:

0.000990

AC XY:

134

AN XY:

135320

show subpopulations

Gnomad AFR exome

AF:

0.0196

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000553

AC:

808

AN:

1461532

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

336

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0201

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00547

AC:

833

AN:

152336

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0194

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00613

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00149

AC:

181

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Lys31Thr in exon 1 of TPM3: This variant is not expected to have clinical signif icance because it has been identified in 1.9% (81/4196) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs62000429). -

TPM3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Congenital myopathy with fiber type disproportion

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myopathy 4B, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.5

.;H;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.013

D;D;.

Vest4

0.68

MVP

0.95

MPC

2.5

ClinPred

0.048

GERP RS

5.8

Varity_R

0.51

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

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