1-154173056-C-G

Variant names:

Variant summary

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

The NM_152263.4(TPM3):c.495+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,452 control chromosomes in the GnomAD database, including 15,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2166 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13743 hom. )

Consequence

TPM3
NM_152263.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.405

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

congenital myopathy 4A, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
TPM3-related myopathy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
congenital myopathy 4B, autosomal recessive
Inheritance: SD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital fiber-type disproportion myopathy
Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital generalized hypercontractile muscle stiffness syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TPM3 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=-0.9).

BP6

Variant 1-154173056-C-G is Benign according to our data. Variant chr1-154173056-C-G is described in ClinVar as Benign. ClinVar VariationId is 262624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM3	NM_152263.4 link	c.495+28G>C		intron_variant	Intron 4 of 9	ENST00000651641.1	NP_689476.2	P06753-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1 link	c.495+28G>C		intron_variant	Intron 4 of 9		NM_152263.4	ENSP00000498577.1		P06753-1

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23300

AN:

152030

Hom.:

2165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.136

AC:

34239

AN:

251476

AF XY:

0.134

show subpopulations

Gnomad AFR exome

AF:

0.230

Gnomad AMR exome

AF:

0.0566

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.373

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.128

AC:

186581

AN:

1461304

Hom.:

13743

Cov.:

AF XY:

0.127

AC XY:

92254

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.221

AC:

7390

AN:

33460

American (AMR)

AF:

0.0604

AC:

2701

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0707

AC:

1847

AN:

26132

East Asian (EAS)

AF:

0.381

AC:

15119

AN:

39696

South Asian (SAS)

AF:

0.129

AC:

11122

AN:

86244

European-Finnish (FIN)

AF:

0.176

AC:

9424

AN:

53418

Middle Eastern (MID)

AF:

0.107

AC:

616

AN:

5766

European-Non Finnish (NFE)

AF:

0.117

AC:

130223

AN:

1111492

Other (OTH)

AF:

0.135

AC:

8139

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

8845

17690

26535

35380

44225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5050

10100

15150

20200

25250

<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:

0.153

AC:

23316

AN:

152148

Hom.:

2166

Cov.:

AF XY:

0.155

AC XY:

11553

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.221

AC:

9171

AN:

41498

American (AMR)

AF:

0.0936

AC:

1431

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0695

AC:

241

AN:

3468

East Asian (EAS)

AF:

0.369

AC:

1906

AN:

5168

South Asian (SAS)

AF:

0.133

AC:

644

AN:

4826

European-Finnish (FIN)

AF:

0.194

AC:

2048

AN:

10576

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7496

AN:

68000

Other (OTH)

AF:

0.131

AC:

277

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

977

1955

2932

3910

4887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.0587

Hom.:

Bravo

AF:

0.149

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

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

-0.90

CADD

Benign

0.079

(source)

DANN

Benign

0.40

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(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