6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATATATATATATA

Variant names:

• chr6-116732074-T-TTATATATATATATATA
• rs2243369
• NM_001366306.2:c.1433-29_1433-14dupTATATATATATATATA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001366306.2(KPNA5):​c.1433-29_1433-14dupTATATATATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.0014 (2 hom., cov: 12)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366306.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA5	NM_001366306.2	MANE Select	c.1433-29_1433-14dupTATATATATATATATA		intron	N/A	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.1493-29_1493-14dupTATATATATATATATA		intron	N/A	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.1493-29_1493-14dupTATATATATATATATA		intron	N/A	NP_001353234.1	A0A8V8TMV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA5	ENST00000368564.7	TSL:1 MANE Select	c.1433-62_1433-61insTATATATATATATATA		intron	N/A	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.1433-62_1433-61insTATATATATATATATA		intron	N/A	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.1508-62_1508-61insTATATATATATATATA		intron	N/A	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 66 AN: 46868 Hom.: 2 Cov.: 12

Gnomad AFR AF: 0.000827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000858

Gnomad ASJ AF: 0.00211

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00214

Gnomad OTH AF: 0.00160

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 20840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11818

African (AFR) AF: 0.00 AC: 0 AN: 958

American (AMR) AF: 0.00 AC: 0 AN: 722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 976

East Asian (EAS) AF: 0.00 AC: 0 AN: 1050

South Asian (SAS) AF: 0.00 AC: 0 AN: 1632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10868

Other (OTH) AF: 0.00 AC: 0 AN: 982

GnomAD4 genome AF: 0.00141 AC: 66 AN: 46868 Hom.: 2 Cov.: 12 AF XY: 0.00176 AC XY: 38 AN XY: 21540

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

African (AFR) AF: 0.000826 AC: 12 AN: 14530

American (AMR) AF: 0.000858 AC: 4 AN: 4662

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 3 AN: 1420

East Asian (EAS) AF: 0.00 AC: 0 AN: 1428

South Asian (SAS) AF: 0.00 AC: 0 AN: 1448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.00214 AC: 46 AN: 21506

Other (OTH) AF: 0.00159 AC: 1 AN: 628

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000521805), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
BranchPoint Hunter		2.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2243369;

hg19: chr6-117053237;