13-49701881-GCAGGGATCTTCAT-G

Position:

• chr13-49701881-GCAGGGATCTTCAT-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002267.4(KPNA3):​c.1472_1484delATGAAGATCCCTG​(p.Asp491fs) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KPNA3 NM_002267.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

Genes affected

KPNA3 (HGNC:6396): (karyopherin subunit alpha 3) The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.06 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNA3	NM_002267.4	c.1472_1484delATGAAGATCCCTG	p.Asp491fs	frameshift_variant	17/17	ENST00000261667.8	NP_002258.2
KPNA3	XM_017020561.2	c.1400_1412delATGAAGATCCCTG	p.Asp467fs	frameshift_variant	17/17		XP_016876050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA3	ENST00000261667.8	c.1472_1484delATGAAGATCCCTG	p.Asp491fs	frameshift_variant	17/17	1	NM_002267.4	ENSP00000261667.3
KPNA3	ENST00000436760.1	c.230_242delATGAAGATCCCTG	p.Asp77fs	frameshift_variant	3/4	2		ENSP00000393869.1

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 31 amino acids are replaced with 30 different amino acids in a gene for which loss-of-function is not an established mechanism of disease -

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: chr13-50276017;