rs79882576

Positions:

• chr9-35683152-G-A
• chr9-35683152-G-C
• chr9-35683152-G-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.*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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.712

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=-0.32).
• BP6: Variant 9-35683152-G-A is Benign according to our data. Variant chr9-35683152-G-A is described in ClinVar as [Benign]. Clinvar id is 94121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35683152-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.*7C>T		3_prime_UTR_variant	9/9	ENST00000645482.3	NP_003280.2
TPM2	NM_001301227.2	c.*7C>T		3_prime_UTR_variant	9/9		NP_001288156.1
TPM2	NM_001301226.2	c.773-989C>T		intron_variant			NP_001288155.1
TPM2	NM_213674.1	c.773-989C>T		intron_variant			NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.*7C>T		3_prime_UTR_variant	9/9		NM_003289.4	ENSP00000496494	A1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5421 AN: 152150 Hom.: 303 Cov.: 33

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

GnomAD3 exomes AF: 0.00829 AC: 1320 AN: 159324 Hom.: 71 AF XY: 0.00604 AC XY: 506 AN XY: 83826

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 SAS exome AF: 0.000304

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.: 33 AF XY: 0.00307 AC XY: 2120 AN XY: 691070

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00959

GnomAD4 genome AF: 0.0358 AC: 5444 AN: 152266 Hom.: 305 Cov.: 33 AF XY: 0.0338 AC XY: 2517 AN XY: 74450

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0108 Hom.: 37

Bravo AF: 0.0407

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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. -

Arthrogryposis, distal, type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myopathy 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.5
DANN	Benign	0.84

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: rs79882576; hg19: chr9-35683149;