Genetic Variant KPNA5:c.1433-23_1433-14delTATATATATA (chr6-116732074-TTATATATATA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001366306.2(KPNA5):c.1433-23_1433-14delTATATATATA 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 67,632 control chromosomes in the GnomAD database, including 24 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 0.019 ( 24 hom., cov: 0)

Exomes 𝑓: 0.0048 ( 0 hom. )

Consequence

KPNA5
NM_001366306.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

3 publications found

Variant links:

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]

KPNA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0186 (871/46840) while in subpopulation SAS AF = 0.0348 (50/1438). AF 95% confidence interval is 0.0271. There are 24 homozygotes in GnomAd4. There are 423 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA5	NM_001366306.2 link	c.1433-23_1433-14delTATATATATA		intron_variant	Intron 13 of 13	ENST00000368564.7	NP_001353235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA5	ENST00000368564.7 link	c.1433-61_1433-52delTATATATATA		intron_variant	Intron 13 of 13	1	NM_001366306.2	ENSP00000357552.1		O15131

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

868

AN:

46840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.00772

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.00664

Gnomad MID

AF:

0.0357

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0288

GnomAD4 exome

AF:

0.00481

AC:

100

AN:

20792

Hom.:

AF XY:

0.00492

AC XY:

AN XY:

11794

show subpopulations

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

African (AFR)

AF:

0.00313

AC:

AN:

958

American (AMR)

AF:

0.00694

AC:

AN:

720

Ashkenazi Jewish (ASJ)

AF:

0.00307

AC:

AN:

976

East Asian (EAS)

AF:

0.00865

AC:

AN:

1040

South Asian (SAS)

AF:

0.00429

AC:

AN:

1630

European-Finnish (FIN)

AF:

0.00307

AC:

AN:

3578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00544

AC:

AN:

10848

Other (OTH)

AF:

0.00307

AC:

AN:

978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0186

AC:

871

AN:

46840

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

423

AN XY:

21516

show subpopulations

African (AFR)

AF:

0.0194

AC:

281

AN:

14512

American (AMR)

AF:

0.0286

AC:

133

AN:

4650

Ashkenazi Jewish (ASJ)

AF:

0.00772

AC:

AN:

1424

East Asian (EAS)

AF:

0.0105

AC:

AN:

1430

South Asian (SAS)

AF:

0.0348

AC:

AN:

1438

European-Finnish (FIN)

AF:

0.00664

AC:

AN:

1054

Middle Eastern (MID)

AF:

0.0385

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0152

AC:

327

AN:

21514

Other (OTH)

AF:

0.0287

AC:

AN:

628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

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6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over