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. The variant received -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:6
• Conservation: PhyloP100: 1.23
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003289.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	NM_003289.4	MANE Select	c.773-4_773-3dupCC		splice_region intron	N/A	NP_003280.2
	TPM2	NM_001301226.2		c.772+1001_772+1002dupCC		intron	N/A	NP_001288155.1
	TPM2	NM_001301227.2		c.773-4_773-3dupCC		splice_region intron	N/A	NP_001288156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM2	ENST00000645482.3	MANE Select	c.773-3_773-2insCC		splice_region intron	N/A	ENSP00000496494.2
	TPM2	ENST00000378292.9	TSL:1	c.772+1002_772+1003insCC		intron	N/A	ENSP00000367542.3
	TPM2	ENST00000329305.6	TSL:2	c.772+1002_772+1003insCC		intron	N/A	ENSP00000367541.1

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

GnomAD2 exomes AF: 0.0322 AC: 4958 AN: 154034 AF XY: 0.0298

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.131 AC: 3830 AN: 29152

American (AMR) AF: 0.0262 AC: 926 AN: 35316

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 676 AN: 24224

East Asian (EAS) AF: 0.00119 AC: 42 AN: 35348

South Asian (SAS) AF: 0.0122 AC: 953 AN: 78130

European-Finnish (FIN) AF: 0.0214 AC: 1023 AN: 47742

Middle Eastern (MID) AF: 0.0254 AC: 139 AN: 5476

European-Non Finnish (NFE) AF: 0.0357 AC: 36128 AN: 1012114

Other (OTH) AF: 0.0356 AC: 1958 AN: 55056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.179 AC: 7250 AN: 40480

American (AMR) AF: 0.0544 AC: 825 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3460

East Asian (EAS) AF: 0.000979 AC: 5 AN: 5106

South Asian (SAS) AF: 0.0139 AC: 66 AN: 4760

European-Finnish (FIN) AF: 0.0298 AC: 310 AN: 10386

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3114 AN: 67606

Other (OTH) AF: 0.0699 AC: 146 AN: 2088

Alfa AF: 0.0332 Hom.: 621

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35401252; hg19: chr9-35683240;