rs202115978

Variant names:

• chr13-49721985-A-T
• rs202115978
• NM_002267.4:c.696T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-49721985-A-T
• chr13-49721985-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002267.4(KPNA3):​c.696T>A​(p.Asp232Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,602,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KPNA3 NM_002267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.489
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spastic paraplegia 88, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1751808).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002267.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA3	NM_002267.4	MANE Select	c.696T>A	p.Asp232Glu	missense	Exon 9 of 17	NP_002258.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA3	ENST00000261667.8	TSL:1 MANE Select	c.696T>A	p.Asp232Glu	missense	Exon 9 of 17	ENSP00000261667.3	O00505
	KPNA3	ENST00000912491.1		c.696T>A	p.Asp232Glu	missense	Exon 10 of 18	ENSP00000582550.1
	KPNA3	ENST00000950770.1		c.696T>A	p.Asp232Glu	missense	Exon 10 of 18	ENSP00000620829.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244488 AF XY: 0.00000756

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1450518 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721312

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.00 AC: 0 AN: 43064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 83930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1106556

Other (OTH) AF: 0.00 AC: 0 AN: 59926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00124846), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151906 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74186

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000149 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.49
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.068	T
Sift4G	Uncertain	0.060	T
Polyphen		0.060	B
Vest4		0.54
MutPred		0.46		Gain of catalytic residue at P233 (P = 0)
MVP		0.61
MPC		1.1
ClinPred		0.45	T
GERP RS		-0.37
Varity_R		0.15
gMVP		0.13
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs202115978; hg19: chr13-50296121;