13-49732764-G-C

Position:

• chr13-49732764-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002267.4(KPNA3):​c.217C>G​(p.Leu73Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,422,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KPNA3 NM_002267.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73

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 Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38289484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KPNA3	NM_002267.4	c.217C>G	p.Leu73Val	missense_variant	4/17	ENST00000261667.8
KPNA3	XM_017020561.2	c.145C>G	p.Leu49Val	missense_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KPNA3	ENST00000261667.8	c.217C>G	p.Leu73Val	missense_variant	4/17	1	NM_002267.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1422274 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 708436

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: 0.00000277

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.037
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.084
Sift	Benign	0.53	T
Sift4G	Benign	0.20	T
Polyphen		0.055	B
Vest4		0.60
MutPred		0.36		Gain of catalytic residue at N70 (P = 5e-04);
MVP		0.68
MPC		1.0
ClinPred		0.67	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs1954482042; hg19: chr13-50306900;