6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATA

Variant names:

• chr6-116732074-T-TTATATA
• rs2243369
• NM_001366306.2:c.1433-19_1433-14dupTATATA

Variant summary

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

The NM_001366306.2(KPNA5):​c.1433-19_1433-14dupTATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 67,242 control chromosomes in the GnomAD database, including 89 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 (89 hom., cov: 12)
  • Exomes 𝑓: 0.00072 (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 89 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.1433-19_1433-14dupTATATA		intron	N/A	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.1493-19_1493-14dupTATATA		intron	N/A	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.1493-19_1493-14dupTATATA		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_1433-61insTATATA		intron	N/A	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.1433-62_1433-61insTATATA		intron	N/A	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.1508-62_1508-61insTATATA		intron	N/A	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 952 AN: 46432 Hom.: 89 Cov.: 12

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.0146

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0194

GnomAD4 exome AF: 0.000721 AC: 15 AN: 20808 Hom.: 0 AF XY: 0.00102 AC XY: 12 AN XY: 11796

⚠️ 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: 956

American (AMR) AF: 0.00 AC: 0 AN: 720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 974

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

South Asian (SAS) AF: 0.000613 AC: 1 AN: 1632

European-Finnish (FIN) AF: 0.00195 AC: 7 AN: 3584

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

European-Non Finnish (NFE) AF: 0.000645 AC: 7 AN: 10848

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000307979), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0205 AC: 952 AN: 46434 Hom.: 89 Cov.: 12 AF XY: 0.0203 AC XY: 434 AN XY: 21328

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

African (AFR) AF: 0.00885 AC: 128 AN: 14466

American (AMR) AF: 0.0167 AC: 77 AN: 4612

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 51 AN: 1404

East Asian (EAS) AF: 0.0237 AC: 33 AN: 1392

South Asian (SAS) AF: 0.0146 AC: 21 AN: 1438

European-Finnish (FIN) AF: 0.00668 AC: 7 AN: 1048

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

European-Non Finnish (NFE) AF: 0.0293 AC: 622 AN: 21260

Other (OTH) AF: 0.0193 AC: 12 AN: 622

⚠️ 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;