Genetic Variant KPNA1:p.Arg395Arg (chr3-122433726-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_002264.4(KPNA1):c.1185G>A(p.Arg395Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,390 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 7 hom., cov: 33)

Exomes 𝑓: 0.012 ( 106 hom. )

Consequence

KPNA1
NM_002264.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.593

Publications

5 publications found

Variant links:

Genes affected

KPNA1 (HGNC:6394): (karyopherin subunit alpha 1) 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. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. This protein interacts with the recombination activating gene 1 (RAG1) protein and is a putative substrate of the RAG1 ubiquitin ligase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

KPNA1 links:

WDR5B-DT (HGNC:55192): (WDR5B divergent transcript)

WDR5B-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 3-122433726-C-T is Benign according to our data. Variant chr3-122433726-C-T is described in ClinVar as [Benign]. Clinvar id is 774847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.593 with no splicing effect.

BS2

High AC in GnomAd4 at 1315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA1	NM_002264.4 link	c.1185G>A	p.Arg395Arg	synonymous_variant	Exon 12 of 14	ENST00000344337.11	NP_002255.3	P52294

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA1	ENST00000344337.11 link	c.1185G>A	p.Arg395Arg	synonymous_variant	Exon 12 of 14	1	NM_002264.4	ENSP00000343701.6		P52294

Frequencies

GnomAD3 genomes

AF:

0.00865

AC:

1316

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00845

AC:

2121

AN:

250916

AF XY:

0.00868

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00410

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00947

GnomAD4 exome

AF:

0.0115

AC:

16876

AN:

1461170

Hom.:

106

Cov.:

AF XY:

0.0112

AC XY:

8140

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33444

American (AMR)

AF:

0.00464

AC:

207

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.0270

AC:

705

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00454

AC:

391

AN:

86156

European-Finnish (FIN)

AF:

0.00318

AC:

170

AN:

53398

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0132

AC:

14658

AN:

1111620

Other (OTH)

AF:

0.0104

AC:

627

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

802

1604

2407

3209

4011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00864

AC:

1315

AN:

152220

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

578

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41542

American (AMR)

AF:

0.00595

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00311

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

917

AN:

68012

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00899

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.2

(source)

DANN

Benign

0.62

PhyloP100

-0.59

Mutation Taster

=98/2

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

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3-122433726-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over