6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATATATA

Position:

• chr6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATATATA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001366306.2(KPNA5):​c.1433-23_1433-14dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0089 in 67,294 control chromosomes in the GnomAD database, including 33 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 12)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: KPNA5 NM_001366306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

Genes affected

KPNA5 (HGNC:6398): (karyopherin subunit alpha 5) 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 and is probably 120 million daltons in molecular size. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion; larger molecules are transported by an active process. Most nuclear proteins contain short basic amino acid sequences known as nuclear localization signals (NLSs). KPNA5 protein belongs to the importin alpha protein family and is thought to be involved in NLS-dependent protein import into the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (592/46482) while in subpopulation NFE AF= 0.0205 (435/21260). AF 95% confidence interval is 0.0189. There are 33 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 12. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPNA5	NM_001366306.2	c.1433-23_1433-14dup		intron_variant		ENST00000368564.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPNA5	ENST00000368564.7	c.1433-23_1433-14dup		intron_variant		1	NM_001366306.2	P4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 591 AN: 46484 Hom.: 33 Cov.: 12

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00714

Gnomad AMR AF: 0.00476

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.00627

Gnomad FIN AF: 0.00485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.00641

GnomAD4 exome AF: 0.000336 AC: 7 AN: 20812 Hom.: 0 AF XY: 0.000170 AC XY: 2 AN XY: 11798

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0127 AC: 592 AN: 46482 Hom.: 33 Cov.: 12 AF XY: 0.0113 AC XY: 241 AN XY: 21368

Gnomad4 AFR AF: 0.00586

Gnomad4 AMR AF: 0.00476

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00628

Gnomad4 FIN AF: 0.00485

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.00639

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		2.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2243369; hg19: chr6-117053237;