13-49732392-T-C

Position:

• chr13-49732392-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_002267.4(KPNA3):​c.362A>G​(p.Lys121Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00945 in 1,574,756 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (90 hom.)
• Consequence: KPNA3 NM_002267.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.24

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 Benign. Variant got -13 ACMG points.

• 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=0.010570794).
• BP6: Variant 13-49732392-T-C is Benign according to our data. Variant chr13-49732392-T-C is described in ClinVar as [Benign]. Clinvar id is 2643818.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00927 (13192/1422486) while in subpopulation MID AF= 0.035 (198/5652). AF 95% confidence interval is 0.031. There are 90 homozygotes in gnomad4_exome. There are 6453 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNA3	NM_002267.4	c.362A>G	p.Lys121Arg	missense_variant	6/17	ENST00000261667.8	NP_002258.2
KPNA3	XM_017020561.2	c.290A>G	p.Lys97Arg	missense_variant	6/17		XP_016876050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA3	ENST00000261667.8	c.362A>G	p.Lys121Arg	missense_variant	6/17	1	NM_002267.4	ENSP00000261667	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152152 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00856 AC: 2099 AN: 245118 Hom.: 15 AF XY: 0.00850 AC XY: 1127 AN XY: 132584

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00921

GnomAD4 exome AF: 0.00927 AC: 13192 AN: 1422486 Hom.: 90 Cov.: 24 AF XY: 0.00911 AC XY: 6453 AN XY: 708342

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.00634

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00979

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.0111 AC: 1685 AN: 152270 Hom.: 12 Cov.: 32 AF XY: 0.0114 AC XY: 846 AN XY: 74458

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0162

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0110 Hom.: 20

Bravo AF: 0.0116

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0103 AC: 88

ExAC AF: 0.00816 AC: 990

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

KPNA3: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.00054
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.44
MVP		0.47
MPC		0.91
ClinPred		0.021	T
GERP RS		6.1
Varity_R		0.097
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

Other links and lift over

dbSNP: rs34024081; hg19: chr13-50306528; COSMIC: COSV99079494;