13-49709678-C-T

Position:

• chr13-49709678-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The ENST00000261667.8(KPNA3):​c.926G>A​(p.Gly309Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KPNA3 ENST00000261667.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest NLS binding site (minor) (size 88) in uniprot entity IMA4_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000261667.8
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNA3	NM_002267.4	c.926G>A	p.Gly309Asp	missense_variant	12/17	ENST00000261667.8	NP_002258.2
KPNA3	XM_017020561.2	c.854G>A	p.Gly285Asp	missense_variant	12/17		XP_016876050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA3	ENST00000261667.8	c.926G>A	p.Gly309Asp	missense_variant	12/17	1	NM_002267.4	ENSP00000261667	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.926G>A (p.G309D) alteration is located in exon 12 (coding exon 12) of the KPNA3 gene. This alteration results from a G to A substitution at nucleotide position 926, causing the glycine (G) at amino acid position 309 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.83		Loss of methylation at R306 (P = 0.0509);
MVP		0.90
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr13-50283814;