Genetic Variant KPNA5:c.1433-23_1433-14dupTATATATATA (chr6-116732074-T-TTATATATATA) – ACMG Classification: Likely_benign (-4 pts)

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

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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA5	NM_001366306.2 link	c.1433-23_1433-14dupTATATATATA		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.1433-62_1433-61insTATATATATA		intron_variant	Intron 13 of 13	1	NM_001366306.2	ENSP00000357552.1		O15131

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

591

AN:

46484

Hom.:

Cov.:

show subpopulations

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:

AN:

20812

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

11798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

958

American (AMR)

AF:

0.00

AC:

AN:

722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

974

East Asian (EAS)

AF:

0.00

AC:

AN:

1050

South Asian (SAS)

AF:

0.00

AC:

AN:

1630

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

3578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000184

AC:

AN:

10854

Other (OTH)

AF:

0.00

AC:

AN:

982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0127

AC:

592

AN:

46482

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

241

AN XY:

21368

show subpopulations

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

African (AFR)

AF:

0.00586

AC:

AN:

14494

American (AMR)

AF:

0.00476

AC:

AN:

4624

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

AN:

1418

East Asian (EAS)

AF:

0.0114

AC:

AN:

1404

South Asian (SAS)

AF:

0.00628

AC:

AN:

1434

European-Finnish (FIN)

AF:

0.00485

AC:

AN:

1030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0205

AC:

435

AN:

21260

Other (OTH)

AF:

0.00639

AC:

AN:

626

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.356

Heterozygous variant carriers

109

136

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

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-116732074-TTATATATATATATATATATATATATATATATATATATATATA-TTATATATATATATATATATATATATATATATATATATATATATATATATATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over