rs147552597

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001145715.3(KPNA7):c.901A>T(p.Thr301Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,547,248 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T301I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 13 hom. )

Consequence

KPNA7
NM_001145715.3 missense, splice_region

Scores

Splicing: ADA: 0.02611

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.45

Variant links:

Genes affected

KPNA7 (HGNC:21839): (karyopherin subunit alpha 7) 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, but exhibits different nuclear localization signal binding specificity compared to other members of the family. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Jul 2016]

KPNA7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009246469).

BP6

Variant 7-99185162-T-A is Benign according to our data. Variant chr7-99185162-T-A is described in ClinVar as [Benign]. Clinvar id is 415823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00589 (894/151864) while in subpopulation AFR AF= 0.0204 (845/41430). AF 95% confidence interval is 0.0193. There are 9 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPNA7	NM_001145715.3 linkuse as main transcript	c.901A>T	p.Thr301Ser	missense_variant, splice_region_variant	8/11	ENST00000327442.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPNA7	ENST00000327442.7 linkuse as main transcript	c.901A>T	p.Thr301Ser	missense_variant, splice_region_variant	8/11	1	NM_001145715.3	P1
KPNA7	ENST00000681060.1 linkuse as main transcript	c.901A>T	p.Thr301Ser	missense_variant, splice_region_variant	8/11			P1

Frequencies

GnomAD3 genomes

AF:

0.00590

AC:

895

AN:

151746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00270

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00107

AC:

167

AN:

155766

Hom.:

AF XY:

0.000814

AC XY:

AN XY:

82342

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000540

AC:

753

AN:

1395384

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

308

AN XY:

688564

show subpopulations

Gnomad4 AFR exome

AF:

0.0203

Gnomad4 AMR exome

AF:

0.000898

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000558

Gnomad4 OTH exome

AF:

0.00117

GnomAD4 genome

AF:

0.00589

AC:

894

AN:

151864

Hom.:

Cov.:

AF XY:

0.00558

AC XY:

414

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0204

Gnomad4 AMR

AF:

0.00269

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00197

Hom.:

Bravo

AF:

0.00655

ESP6500AA

AF:

0.0188

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00230

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

KPNA7-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

Eigen

Benign

0.18

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.044

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.32

Sift

Uncertain

0.016

Sift4G

Benign

0.068

Polyphen

1.0

Vest4

0.33

MutPred

0.47

Gain of disorder (P = 0.0436);

MVP

0.36

ClinPred

0.056

GERP RS

4.4

Varity_R

0.47

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.026

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.44

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over