7-128957252-GAGCTATCGAA-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012470.4(TNPO3):c.2765_*2del variant causes a stop lost, 3 prime UTR 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO3 NM_012470.4 stop_lost, 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO3	NM_012470.4	c.2765_*2del		stop_lost, 3_prime_UTR_variant	22/23	ENST00000265388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO3	ENST00000265388.10	c.2765_*2del		stop_lost, 3_prime_UTR_variant	22/23	1	NM_012470.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein elongation as the last 3 amino acids are lost and replaced with 14 incorrect amino acids; Has not been previously published as pathogenic or benign to our knowledge; A nearby overlapping frameshift variant (c.2771delA) has been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2014) -

Autosomal dominant limb-girdle muscular dystrophy type 1F Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 25, 2022

This variant has not been reported in the literature in individuals affected with TNPO3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1308080). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the TNPO3 mRNA. It is expected to extend the length of the TNPO3 protein by 12 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128597306;