chr6-116732074-T-TTATATATATA

Variant names:

• chr6-116732074-T-TTATATATATA
• rs2243369
• NM_001366306.2:c.1433-23_1433-14dupTATATATATA

Variant summary

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

The NM_001366306.2(KPNA5):​c.1433-23_1433-14dupTATATATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0089 in 67,294 control chromosomes in the GnomAD database, including 33 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 0.013 (33 hom., cov: 12)
  • Exomes 𝑓: 0.00034 (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 33 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.1433-23_1433-14dupTATATATATA		intron	N/A	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.1493-23_1493-14dupTATATATATA		intron	N/A	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.1493-23_1493-14dupTATATATATA		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_1433-61insTATATATATA		intron	N/A	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.1433-62_1433-61insTATATATATA		intron	N/A	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.1508-62_1508-61insTATATATATA		intron	N/A	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 591 AN: 46484 Hom.: 33 Cov.: 12

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00714

Gnomad AMR AF: 0.00476

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.00627

Gnomad FIN AF: 0.00485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.00641

GnomAD4 exome AF: 0.000336 AC: 7 AN: 20812 Hom.: 0 AF XY: 0.000170 AC XY: 2 AN XY: 11798

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: 974

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

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: 0.000184 AC: 2 AN: 10854

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

GnomAD4 genome AF: 0.0127 AC: 592 AN: 46482 Hom.: 33 Cov.: 12 AF XY: 0.0113 AC XY: 241 AN XY: 21368

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

African (AFR) AF: 0.00586 AC: 85 AN: 14494

American (AMR) AF: 0.00476 AC: 22 AN: 4624

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 15 AN: 1418

East Asian (EAS) AF: 0.0114 AC: 16 AN: 1404

South Asian (SAS) AF: 0.00628 AC: 9 AN: 1434

European-Finnish (FIN) AF: 0.00485 AC: 5 AN: 1030

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

European-Non Finnish (NFE) AF: 0.0205 AC: 435 AN: 21260

Other (OTH) AF: 0.00639 AC: 4 AN: 626

⚠️ 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
Mutation Taster		=100/0	polymorphism

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;