Variant 13-49709621-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5

The NM_002267.4(KPNA3):c.983T>C(p.Leu328Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L328M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KPNA3
NM_002267.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.25

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_002267.4 (KPNA3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 13-49709621-A-G is Pathogenic according to our data. Variant chr13-49709621-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1713275.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNA3	NM_002267.4 link	c.983T>C	p.Leu328Pro	missense_variant	12/17	ENST00000261667.8	NP_002258.2	O00505A0A024RDV7
KPNA3	XM_017020561.2 link	c.911T>C	p.Leu304Pro	missense_variant	12/17		XP_016876050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA3	ENST00000261667.8 link	c.983T>C	p.Leu328Pro	missense_variant	12/17	1	NM_002267.4	ENSP00000261667.3		O00505

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spastic paraplegia 88, autosomal dominant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

0.78

Vest4

0.96

MutPred

0.66

Gain of catalytic residue at V327 (P = 0.0084);

MVP

0.91

MPC

1.6

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over