9-35683243-TGGGGGG-TGGGGGGGG

Variant names:

• chr9-35683243-T-TGG
• rs35401252
• NM_003289.4:c.773-4_773-3dupCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003289.4(TPM2):​c.773-4_773-3dupCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,472,824 control chromosomes in the GnomAD database, including 899 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (770 hom., cov: 0)
  • Exomes 𝑓: 0.035 (129 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23

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 -16 ACMG points.

• BP6: Variant 9-35683243-T-TGG is Benign according to our data. Variant chr9-35683243-T-TGG is described in ClinVar as [Likely_benign]. Clinvar id is 94125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.773-4_773-3dupCC		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000645482.3	NP_003280.2
TPM2	NM_001301226.2	c.772+1001_772+1002dupCC		intron_variant	Intron 8 of 8		NP_001288155.1
TPM2	NM_001301227.2	c.773-4_773-3dupCC		splice_region_variant, intron_variant	Intron 8 of 8		NP_001288156.1
TPM2	NM_213674.1	c.772+1001_772+1002dupCC		intron_variant	Intron 8 of 8		NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.773-3_773-2insCC		splice_region_variant, intron_variant	Intron 8 of 8		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.0788 AC: 11831 AN: 150148 Hom.: 769 Cov.: 0

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.000977

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.0322 AC: 4958 AN: 154034 Hom.: 1 AF XY: 0.0298 AC XY: 2418 AN XY: 81146

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.00192

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0345 AC: 45675 AN: 1322558 Hom.: 129 Cov.: 34 AF XY: 0.0339 AC XY: 22169 AN XY: 654466

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0262

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00119

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0357

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0788 AC: 11848 AN: 150266 Hom.: 770 Cov.: 0 AF XY: 0.0764 AC XY: 5606 AN XY: 73416

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0544

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.000979

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0298

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 21, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 1A;C0546264:Congenital myopathy with fiber type disproportion;C1836447:Congenital myopathy 23 Benign:1

Mar 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 1A Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35401252; hg19: chr9-35683240;