dbSNP rs2305402: KPNA4:c.1138-48T>G (chr3-160509919-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002268.5(KPNA4):c.1138-48T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,188,270 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 57 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 85 hom. )

Consequence

KPNA4
NM_002268.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.05

Publications

3 publications found

Variant links:

Genes affected

KPNA4 (HGNC:6397): (karyopherin subunit alpha 4) The nuclear import of karyophilic proteins is directed by short amino acid sequences termed nuclear localization signals (NLSs). Karyopherins, or importins, are cytoplasmic proteins that recognize NLSs and dock NLS-containing proteins to the nuclear pore complex. The protein encoded by this gene shares the sequence similarity with Xenopus importin-alpha and Saccharomyces cerevisiae Srp1. This protein is found to interact with the NLSs of DNA helicase Q1 and SV40 T antigen. [provided by RefSeq, Jul 2008]

KPNA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0167 (2537/152294) while in subpopulation AFR AF = 0.0461 (1917/41556). AF 95% confidence interval is 0.0444. There are 57 homozygotes in GnomAd4. There are 1246 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2537 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA4	NM_002268.5 link	c.1138-48T>G		intron_variant	Intron 13 of 16	ENST00000334256.9	NP_002259.1	O00629

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA4	ENST00000334256.9 link	c.1138-48T>G		intron_variant	Intron 13 of 16	1	NM_002268.5	ENSP00000334373.4		O00629

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2518

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.0283

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00812

AC:

1900

AN:

234118

AF XY:

0.00702

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00612

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.0249

Gnomad FIN exome

AF:

0.000566

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00840

GnomAD4 exome

AF:

0.00576

AC:

5970

AN:

1035976

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

2972

AN XY:

533672

show subpopulations

African (AFR)

AF:

0.0469

AC:

1129

AN:

24078

American (AMR)

AF:

0.00689

AC:

267

AN:

38776

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

271

AN:

22770

East Asian (EAS)

AF:

0.0392

AC:

1477

AN:

37656

South Asian (SAS)

AF:

0.00371

AC:

274

AN:

73862

European-Finnish (FIN)

AF:

0.000586

AC:

AN:

52896

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00271

AC:

1995

AN:

735282

Other (OTH)

AF:

0.00995

AC:

457

AN:

45940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

294

588

883

1177

1471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.0167

AC:

2537

AN:

152294

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1246

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0461

AC:

1917

AN:

41556

American (AMR)

AF:

0.0112

AC:

172

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.0284

AC:

147

AN:

5184

South Asian (SAS)

AF:

0.00352

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00291

AC:

198

AN:

68024

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0105

Hom.:

Bravo

AF:

0.0192

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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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