6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATA

Variant names:

• chr6-116732074-TTATATATATATA-T
• rs2243369
• NM_001366306.2:c.1433-25_1433-14delTATATATATATA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001366306.2(KPNA5):​c.1433-25_1433-14delTATATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 67,604 control chromosomes in the GnomAD database, including 41 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 0.025 (39 hom., cov: 0)
  • Exomes 𝑓: 0.012 (2 hom.)
• Consequence: KPNA5 NM_001366306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0246 (1154/46852) while in subpopulation SAS AF = 0.0589 (85/1442). AF 95% confidence interval is 0.0488. There are 39 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA5	NM_001366306.2	c.1433-25_1433-14delTATATATATATA		intron_variant	Intron 13 of 13	ENST00000368564.7	NP_001353235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA5	ENST00000368564.7	c.1433-61_1433-50delTATATATATATA		intron_variant	Intron 13 of 13	1	NM_001366306.2	ENSP00000357552.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 1153 AN: 46852 Hom.: 39 Cov.: 0

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00714

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0310

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0589

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0208

GnomAD4 exome AF: 0.0117 AC: 243 AN: 20752 Hom.: 2 AF XY: 0.0125 AC XY: 147 AN XY: 11764

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

African (AFR) AF: 0.00523 AC: 5 AN: 956

American (AMR) AF: 0.0252 AC: 18 AN: 714

Ashkenazi Jewish (ASJ) AF: 0.00821 AC: 8 AN: 974

East Asian (EAS) AF: 0.00575 AC: 6 AN: 1044

South Asian (SAS) AF: 0.0123 AC: 20 AN: 1626

European-Finnish (FIN) AF: 0.0109 AC: 39 AN: 3568

Middle Eastern (MID) AF: 0.0156 AC: 1 AN: 64

European-Non Finnish (NFE) AF: 0.0119 AC: 129 AN: 10828

Other (OTH) AF: 0.0174 AC: 17 AN: 978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0246 AC: 1154 AN: 46852 Hom.: 39 Cov.: 0 AF XY: 0.0248 AC XY: 535 AN XY: 21530

African (AFR) AF: 0.0177 AC: 257 AN: 14518

American (AMR) AF: 0.0331 AC: 154 AN: 4656

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 44 AN: 1420

East Asian (EAS) AF: 0.00839 AC: 12 AN: 1430

South Asian (SAS) AF: 0.0589 AC: 85 AN: 1442

European-Finnish (FIN) AF: 0.0247 AC: 26 AN: 1054

Middle Eastern (MID) AF: 0.0192 AC: 1 AN: 52

European-Non Finnish (NFE) AF: 0.0261 AC: 561 AN: 21514

Other (OTH) AF: 0.0208 AC: 13 AN: 626

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2243369; hg19: chr6-117053237;