rs754311223

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001145715.3(KPNA7):c.631C>G(p.Leu211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,500,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L211R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

KPNA7
NM_001145715.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0270

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

oocyte/zygote/embryo maturation arrest 17
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KPNA7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010759205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA7	NM_001145715.3 link	c.631C>G	p.Leu211Val	missense_variant	Exon 6 of 11	ENST00000327442.7	NP_001139187.1	A9QM74

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA7	ENST00000327442.7 link	c.631C>G	p.Leu211Val	missense_variant	Exon 6 of 11	1	NM_001145715.3	ENSP00000330878.6		A9QM74
KPNA7	ENST00000681060.1 link	c.631C>G	p.Leu211Val	missense_variant	Exon 6 of 11			ENSP00000506489.1		A9QM74

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151960

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:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000250

AC:

AN:

120132

AF XY:

0.000328

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:

0.00

Gnomad OTH exome

AF:

0.000317

GnomAD4 exome

AF:

0.0000831

AC:

112

AN:

1348006

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

663844

show subpopulations

African (AFR)

AF:

0.0000351

AC:

AN:

28494

American (AMR)

AF:

0.00

AC:

AN:

25156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23358

East Asian (EAS)

AF:

0.00

AC:

AN:

34542

South Asian (SAS)

AF:

0.00152

AC:

104

AN:

68636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5424

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059212

Other (OTH)

AF:

0.000126

AC:

AN:

55490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41528

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 211 of the KPNA7 protein (p.Leu211Val). This variant is present in population databases (rs754311223, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with KPNA7-related conditions. ClinVar contains an entry for this variant (Variation ID: 238563). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.024

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.076

M_CAP

Benign

0.019

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.075

PhyloP100

-0.027

PrimateAI

Benign

0.30

PROVEAN

Benign

0.060

REVEL

Benign

0.030

Sift

Benign

0.23

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.039

MutPred

0.43

Gain of glycosylation at T210 (P = 0.0999);

MVP

0.055

ClinPred

0.056

GERP RS

-0.14

Varity_R

0.043

gMVP

0.087

Mutation Taster

=94/6

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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rs754311223

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