Genetic Variant KPNA5:c.1433-17_1433-14dupTATA (chr6-116732074-T-TTATA) – 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.1433-17_1433-14dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 67,284 control chromosomes in the GnomAD database, including 34 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 0.017 ( 34 hom., cov: 12)

Exomes 𝑓: 0.0010 ( 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 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA5	NM_001366306.2 link	c.1433-17_1433-14dupTATA		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_1433-61insTATA		intron_variant	Intron 13 of 13	1	NM_001366306.2	ENSP00000357552.1		O15131

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

799

AN:

46492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00831

Gnomad AMI

AF:

0.0145

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0388

Gnomad EAS

AF:

0.0134

Gnomad SAS

AF:

0.00772

Gnomad FIN

AF:

0.00381

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0227

GnomAD4 exome

AF:

0.00101

AC:

AN:

20792

Hom.:

AF XY:

0.00102

AC XY:

AN XY:

11782

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

958

American (AMR)

AF:

0.00139

AC:

AN:

720

Ashkenazi Jewish (ASJ)

AF:

0.00307

AC:

AN:

976

East Asian (EAS)

AF:

0.00

AC:

AN:

1048

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:

0.00101

AC:

AN:

10838

Other (OTH)

AF:

0.00102

AC:

AN:

980

⚠️ 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: 0.299

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:

0.0172

AC:

799

AN:

46492

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

370

AN XY:

21366

show subpopulations

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

African (AFR)

AF:

0.00830

AC:

120

AN:

14454

American (AMR)

AF:

0.0183

AC:

AN:

4596

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

AN:

1418

East Asian (EAS)

AF:

0.0135

AC:

AN:

1404

South Asian (SAS)

AF:

0.00702

AC:

AN:

1424

European-Finnish (FIN)

AF:

0.00381

AC:

AN:

1050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0230

AC:

491

AN:

21336

Other (OTH)

AF:

0.0226

AC:

AN:

620

⚠️ 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: 0.374

Heterozygous variant carriers

115

154

192

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-TTATATATATATATATATATATATATATATATATATATATATATATA

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