Genetic Variant KPNA5:p.Ile526Thr (chr6-116732280-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366306.2(KPNA5):c.1577T>C(p.Ile526Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,538,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

KPNA5
NM_001366306.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.47

Publications

2 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11397889).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KPNA5	NM_001366306.2	MANE Select	c.1577T>C	p.Ile526Thr	missense	Exon 14 of 14	NP_001353235.1	O15131
KPNA5	NM_001366304.1		c.1637T>C	p.Ile546Thr	missense	Exon 15 of 16	NP_001353233.1	A0A8V8TMV2
KPNA5	NM_001366305.2		c.1637T>C	p.Ile546Thr	missense	Exon 15 of 15	NP_001353234.1	A0A8V8TMV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KPNA5	ENST00000368564.7	TSL:1 MANE Select	c.1577T>C	p.Ile526Thr	missense	Exon 14 of 14	ENSP00000357552.1	O15131
KPNA5	ENST00000356348.6	TSL:1	c.1577T>C	p.Ile526Thr	missense	Exon 14 of 15	ENSP00000348704.1	O15131
KPNA5	ENST00000937498.1		c.1652T>C	p.Ile551Thr	missense	Exon 15 of 15	ENSP00000607557.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000232

AC:

AN:

215380

AF XY:

0.0000171

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000495

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1386998

Hom.:

Cov.:

AF XY:

0.0000436

AC XY:

AN XY:

688472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30442

American (AMR)

AF:

0.00

AC:

AN:

37268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24524

East Asian (EAS)

AF:

0.00

AC:

AN:

35652

South Asian (SAS)

AF:

0.00

AC:

AN:

72992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51292

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.0000532

AC:

AN:

1072414

Other (OTH)

AF:

0.0000352

AC:

AN:

56872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.0000132

AC:

AN:

151174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41204

American (AMR)

AF:

0.00

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67670

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000776

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.89

Eigen

Benign

-0.19

Eigen_PC

Benign

0.071

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.0029

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

7.5

PrimateAI

Benign

0.35

PROVEAN

Benign

0.77

REVEL

Benign

0.12

Sift

Benign

0.58

Sift4G

Benign

0.58

Vest4

0.11

MVP

0.50

MPC

0.35

ClinPred

0.22

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.075

Mutation Taster

=66/34

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over