rs4845364

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_152263.4(TPM3):c.776-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,585,680 control chromosomes in the GnomAD database, including 252,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 31391 hom., cov: 32)

Exomes 𝑓: 0.55 ( 221161 hom. )

Consequence

TPM3
NM_152263.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.10

Publications

23 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, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
congenital myopathy 4B, autosomal recessive
Inheritance: SD, AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 1-154169432-A-G is Benign according to our data. Variant chr1-154169432-A-G is described in ClinVar as Benign. ClinVar VariationId is 262627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM3	NM_152263.4	MANE Select	c.776-49T>C	intron	N/A	NP_689476.2	P06753-1
TPM3	NM_001364679.2		c.775+968T>C	intron	N/A	NP_001351608.1
TPM3	NM_001364680.2		c.775+968T>C	intron	N/A	NP_001351609.1	J3KN67

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM3	ENST00000651641.1	MANE Select	c.776-49T>C	intron	N/A	ENSP00000498577.1	P06753-1
TPM3	ENST00000368530.7	TSL:1	c.776-49T>C	intron	N/A	ENSP00000357516.3	A0A2R2Y2Q3
TPM3	ENST00000330188.13	TSL:1	c.664+968T>C	intron	N/A	ENSP00000339035.7	P06753-5

Frequencies

GnomAD3 genomes

AF:

0.627

AC:

95320

AN:

151916

Hom.:

31338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.804

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.679

Gnomad ASJ

AF:

0.523

Gnomad EAS

AF:

0.881

Gnomad SAS

AF:

0.666

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.503

Gnomad OTH

AF:

0.619

GnomAD2 exomes

AF:

0.608

AC:

152237

AN:

250250

AF XY:

0.602

show subpopulations

Gnomad AFR exome

AF:

0.813

Gnomad AMR exome

AF:

0.717

Gnomad ASJ exome

AF:

0.530

Gnomad EAS exome

AF:

0.869

Gnomad FIN exome

AF:

0.553

Gnomad NFE exome

AF:

0.512

Gnomad OTH exome

AF:

0.584

GnomAD4 exome

AF:

0.547

AC:

784078

AN:

1433646

Hom.:

221161

Cov.:

AF XY:

0.548

AC XY:

392075

AN XY:

715072

show subpopulations

African (AFR)

AF:

0.818

AC:

26995

AN:

32986

American (AMR)

AF:

0.716

AC:

31975

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

13509

AN:

25942

East Asian (EAS)

AF:

0.920

AC:

36452

AN:

39614

South Asian (SAS)

AF:

0.641

AC:

54933

AN:

85694

European-Finnish (FIN)

AF:

0.553

AC:

29509

AN:

53334

Middle Eastern (MID)

AF:

0.624

AC:

3569

AN:

5718

European-Non Finnish (NFE)

AF:

0.509

AC:

552634

AN:

1086280

Other (OTH)

AF:

0.580

AC:

34502

AN:

59446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

17823

35646

53470

71293

89116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16116

32232

48348

64464

80580

<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:

0.628

AC:

95428

AN:

152034

Hom.:

31391

Cov.:

AF XY:

0.633

AC XY:

46996

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.805

AC:

33389

AN:

41484

American (AMR)

AF:

0.679

AC:

10369

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

1815

AN:

3470

East Asian (EAS)

AF:

0.882

AC:

4563

AN:

5176

South Asian (SAS)

AF:

0.665

AC:

3205

AN:

4820

European-Finnish (FIN)

AF:

0.571

AC:

6015

AN:

10542

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.503

AC:

34209

AN:

67966

Other (OTH)

AF:

0.616

AC:

1301

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1715

3429

5144

6858

8573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.545

Hom.:

44207

Bravo

AF:

0.647

Asia WGS

AF:

0.753

AC:

2618

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Congenital myopathy 4B, autosomal recessive (1)

Congenital myopathy with fiber type disproportion (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over