6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATA

Variant names:

• chr6-116732074-T-TTA
• rs2243369
• NM_001366306.2:c.1433-15_1433-14dupTA

Variant summary

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

The NM_001366306.2(KPNA5):​c.1433-15_1433-14dupTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 67,412 control chromosomes in the GnomAD database, including 48 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 0.021 (48 hom., cov: 12)
  • Exomes 𝑓: 0.00077 (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 48 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.1433-15_1433-14dupTA		intron	N/A	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.1493-15_1493-14dupTA		intron	N/A	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.1493-15_1493-14dupTA		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_1433-61insTA		intron	N/A	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.1433-62_1433-61insTA		intron	N/A	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.1508-62_1508-61insTA		intron	N/A	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 983 AN: 46600 Hom.: 48 Cov.: 12

Gnomad AFR AF: 0.00810

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.00484

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.000769 AC: 16 AN: 20814 Hom.: 0 AF XY: 0.000762 AC XY: 9 AN XY: 11804

⚠️ 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: 0.00277 AC: 2 AN: 722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 972

East Asian (EAS) AF: 0.000952 AC: 1 AN: 1050

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

European-Finnish (FIN) AF: 0.00140 AC: 5 AN: 3584

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

European-Non Finnish (NFE) AF: 0.000645 AC: 7 AN: 10856

Other (OTH) AF: 0.00102 AC: 1 AN: 978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0211 AC: 983 AN: 46598 Hom.: 48 Cov.: 12 AF XY: 0.0195 AC XY: 417 AN XY: 21416

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

African (AFR) AF: 0.00809 AC: 117 AN: 14462

American (AMR) AF: 0.0199 AC: 92 AN: 4616

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 45 AN: 1416

East Asian (EAS) AF: 0.0178 AC: 25 AN: 1408

South Asian (SAS) AF: 0.00484 AC: 7 AN: 1446

European-Finnish (FIN) AF: 0.0183 AC: 19 AN: 1036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 48

European-Non Finnish (NFE) AF: 0.0310 AC: 664 AN: 21402

Other (OTH) AF: 0.0224 AC: 14 AN: 624

⚠️ 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;