6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATA

Variant names:

• chr6-116732074-T-TTATA
• rs2243369
• NM_001366306.2:c.1433-17_1433-14dupTATA

Variant summary

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

The NM_001366306.2(KPNA5):​c.1433-17_1433-14dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 67,284 control chromosomes in the GnomAD database, including 34 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 0.017 (34 hom., cov: 12)
  • Exomes 𝑓: 0.0010 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 34 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.1433-17_1433-14dupTATA		intron	N/A	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.1493-17_1493-14dupTATA		intron	N/A	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.1493-17_1493-14dupTATA		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_1433-61insTATA		intron	N/A	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.1433-62_1433-61insTATA		intron	N/A	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.1508-62_1508-61insTATA		intron	N/A	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 799 AN: 46492 Hom.: 34 Cov.: 12

Gnomad AFR AF: 0.00831

Gnomad AMI AF: 0.0145

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0388

Gnomad EAS AF: 0.0134

Gnomad SAS AF: 0.00772

Gnomad FIN AF: 0.00381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.00101 AC: 21 AN: 20792 Hom.: 0 AF XY: 0.00102 AC XY: 12 AN XY: 11782

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

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

American (AMR) AF: 0.00139 AC: 1 AN: 720

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 3 AN: 976

East Asian (EAS) AF: 0.00 AC: 0 AN: 1048

South Asian (SAS) AF: 0.00 AC: 0 AN: 1630

European-Finnish (FIN) AF: 0.00140 AC: 5 AN: 3578

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

European-Non Finnish (NFE) AF: 0.00101 AC: 11 AN: 10838

Other (OTH) AF: 0.00102 AC: 1 AN: 980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000579425), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0172 AC: 799 AN: 46492 Hom.: 34 Cov.: 12 AF XY: 0.0173 AC XY: 370 AN XY: 21366

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

African (AFR) AF: 0.00830 AC: 120 AN: 14454

American (AMR) AF: 0.0183 AC: 84 AN: 4596

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 55 AN: 1418

East Asian (EAS) AF: 0.0135 AC: 19 AN: 1404

South Asian (SAS) AF: 0.00702 AC: 10 AN: 1424

European-Finnish (FIN) AF: 0.00381 AC: 4 AN: 1050

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

European-Non Finnish (NFE) AF: 0.0230 AC: 491 AN: 21336

Other (OTH) AF: 0.0226 AC: 14 AN: 620

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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;