9-35683152-G-A

Variant names:

Variant summary

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

The NM_003289.4(TPM2):c.*7C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,553,072 control chromosomes in the GnomAD database, including 565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 305 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 260 hom. )

Consequence

TPM2
NM_003289.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.712

Publications

4 publications found

Variant links:

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

TPM2 Gene-Disease associations (from GenCC):

TPM2-related myopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arthrogryposis, distal, type 1A
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
congenital myopathy 23
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sheldon-hall syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TPM2 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=-0.32).

BP6

Variant 9-35683152-G-A is Benign according to our data. Variant chr9-35683152-G-A is described in ClinVar as Benign. ClinVar VariationId is 94121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.*7C>T	3_prime_UTR_variant	Exon 9 of 9	ENST00000645482.3	NP_003280.2	P07951-1
TPM2	NM_001301227.2 link	c.*7C>T	3_prime_UTR_variant	Exon 9 of 9		NP_001288156.1	A7XZE4V9HW25
TPM2	NM_001301226.2 link	c.773-989C>T	intron_variant	Intron 8 of 8		NP_001288155.1	Q5TCU3V9HW25
TPM2	NM_213674.1 link	c.773-989C>T	intron_variant	Intron 8 of 8		NP_998839.1	P07951-2V9HW25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.*7C>T		3_prime_UTR_variant	Exon 9 of 9		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

AF:

0.0356

AC:

5421

AN:

152150

Hom.:

303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.00829

AC:

1320

AN:

159324

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000868

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000226

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00360

AC:

5038

AN:

1400806

Hom.:

260

Cov.:

AF XY:

0.00307

AC XY:

2120

AN XY:

691070

show subpopulations

African (AFR)

AF:

0.124

AC:

3930

AN:

31642

American (AMR)

AF:

0.00698

AC:

251

AN:

35958

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25266

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35836

South Asian (SAS)

AF:

0.000390

AC:

AN:

79448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49370

Middle Eastern (MID)

AF:

0.00825

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000204

AC:

220

AN:

1079508

Other (OTH)

AF:

0.00959

AC:

557

AN:

58078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

296

592

887

1183

1479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.0358

AC:

5444

AN:

152266

Hom.:

305

Cov.:

AF XY:

0.0338

AC XY:

2517

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.124

AC:

5134

AN:

41516

American (AMR)

AF:

0.0154

AC:

235

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68026

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

229

459

688

918

1147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0126

Hom.:

Bravo

AF:

0.0407

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 29, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2016

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. -

Arthrogryposis, distal, type 1A

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myopathy 23

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

-0.32

CADD

Benign

6.5

(source)

DANN

Benign

0.84

PhyloP100

0.71

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