rs56249943

chr9-35683151-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003289.4(TPM2):c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,552,166 control chromosomes in the GnomAD database, including 6,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (372 hom., cov: 32)
  • Exomes 𝑓: 0.088 (5806 hom.)
• Consequence: TPM2 NM_003289.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.423

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 9-35683151-C-T is Benign according to our data. Variant chr9-35683151-C-T is described in ClinVar as [Benign]. Clinvar id is 94122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683151-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.*8G>A		3_prime_UTR_variant	9/9	ENST00000645482.3
TPM2	NM_001301227.2	c.*8G>A		3_prime_UTR_variant	9/9
TPM2	NM_001301226.2	c.773-988G>A		intron_variant
TPM2	NM_213674.1	c.773-988G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.*8G>A		3_prime_UTR_variant	9/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9609 AN: 152014 Hom.: 372 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0934

Gnomad OTH AF: 0.0692

GnomAD3 exomes AF: 0.0760 AC: 12096 AN: 159072 Hom.: 511 AF XY: 0.0785 AC XY: 6571 AN XY: 83690

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0717

Gnomad ASJ exome AF: 0.0904

Gnomad EAS exome AF: 0.0327

Gnomad SAS exome AF: 0.0835

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0976

Gnomad OTH exome AF: 0.0762

GnomAD4 exome AF: 0.0879 AC: 123047 AN: 1400034 Hom.: 5806 Cov.: 33 AF XY: 0.0885 AC XY: 61092 AN XY: 690674

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0701

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.0840

Gnomad4 FIN exome AF: 0.0466

Gnomad4 NFE exome AF: 0.0953

Gnomad4 OTH exome AF: 0.0837

GnomAD4 genome AF: 0.0632 AC: 9614 AN: 152132 Hom.: 372 Cov.: 32 AF XY: 0.0608 AC XY: 4525 AN XY: 74402

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.0650

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.0285

Gnomad4 SAS AF: 0.0757

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.0935

Gnomad4 OTH AF: 0.0704

Alfa AF: 0.0851 Hom.: 281

Bravo AF: 0.0653

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	*8G>A in exon 9A of TPM2: This variant is not expected to have clinical signific ance because it has been identified in 8.9% (757/8480) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs56249943). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arthrogryposis, distal, type 1A 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 23 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. -

not provided Other:1

not provided, no classification provided

literature only

TPM2 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.65
Dann	Benign	0.85

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

Other links and lift over

dbSNP: rs56249943; hg19: chr9-35683148;