7-128957259-CG-C

Position:

• chr7-128957259-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_012470.4(TNPO3):​c.2767delC​(p.Arg923fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO3 NM_012470.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.14

Genes affected

TNPO3 (HGNC:17103): (transportin 3) The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. The encoded protein has also been shown to be involved in HIV-1 infection, apparently through interaction with the HIV-1 capsid protein. Several protein-coding and non-coding transcript variants have been found for this gene. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0018 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-128957259-CG-C is Pathogenic according to our data. Variant chr7-128957259-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 591000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNPO3	NM_012470.4	c.2767delC	p.Arg923fs	frameshift_variant	22/23	ENST00000265388.10	NP_036602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10	c.2767delC	p.Arg923fs	frameshift_variant	22/23	1	NM_012470.4	ENSP00000265388.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1F Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, University of Pecs	Sep 10, 2018	The c.2767delC (p.Arg923Aspfs*17) variant was predicted to cause truncated protein. Other dominant truncating mutations in the TNPO3 protein are reported to cause Limb-Girdle Muscular Dystrophy type 1F (LGMD1F) (Gamez J. et al. 2001). Segregation analysis confirmed that the same variant is seen in the patient's affected son, and absent in her unaffected son. The variant has not been previously seen in presumed healthy control databases (ExAC, 1000Genomes, EVS). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 09, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant results in an extension of the TNPO3 protein. Other variant(s) that result in a similarly extended protein product (p.*924Cysext*15) have been determined to be pathogenic (PMID: 23543484, 23667635). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 591000). This frameshift has been observed in at least one individual who was not affected with TNPO3-related conditions (Invitae). This frameshift has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 31071488, 31217819). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TNPO3 gene (p.Arg923Aspfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the TNPO3 protein and extend the protein by 15 additional amino acid residues. -

Muscular dystrophy, limb-girdle, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Nov 21, 2024

The heterozygous p.Arg923AspfsTer17 variant was identified by our study in 2 affected siblings with limb-girdle muscular dystrophy. The p.Arg923AspfsTer17 variant has been reported in 2 affected individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 31071488). This variant was absent from large population studies. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 591000) and has been interpreted as likely pathogenic by Labcorp and Department of Medical Genetics (University of Pecs). This variant causes a frameshift which abolishes the native stop codon and extends the protein an additional 15 amino acids. Other c-terminal extending proteins in TNPO3 have been seen in individuals with limb-girlde muscular dystrophy (PMID: 23543484). Heterozygous loss of function of the TNPO3 gene is an established disease mechanism in limb-girdle muscular dystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant limb-girdle muscular dystrophy. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting, PS4_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1563083759; hg19: chr7-128597313;