Variant 13-49709598-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_002267.4(KPNA3):c.1006T>A(p.Ser336Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KPNA3
NM_002267.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46

Variant links:

Genes affected

KPNA3 (HGNC:6396): (karyopherin subunit alpha 3) 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. [provided by RefSeq, Jan 2009]

KPNA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a repeat ARM 7 (size 41) in uniprot entity IMA4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002267.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KPNA3. . Gene score misZ 3.3927 (greater than the threshold 3.09). Trascript score misZ 3.1846 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia 88, autosomal dominant.

BP4

Computational evidence support a benign effect (MetaRNN=0.096096605).

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPNA3	NM_002267.4 linkuse as main transcript	c.1006T>A	p.Ser336Thr	missense_variant	12/17	ENST00000261667.8
KPNA3	XM_017020561.2 linkuse as main transcript	c.934T>A	p.Ser312Thr	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPNA3	ENST00000261667.8 linkuse as main transcript	c.1006T>A	p.Ser336Thr	missense_variant	12/17	1	NM_002267.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251344

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135844

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.1006T>A (p.S336T) alteration is located in exon 12 (coding exon 12) of the KPNA3 gene. This alteration results from a T to A substitution at nucleotide position 1006, causing the serine (S) at amino acid position 336 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.075

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.73

M_CAP

Benign

0.0042

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.13

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.62

REVEL

Benign

0.070

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.13

MutPred

0.47

Loss of disorder (P = 0.0645);

MVP

0.37

MPC

0.89

ClinPred

0.69

GERP RS

3.9

Varity_R

0.062

gMVP

0.20

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

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