chr13-49722025-T-C

Variant names:

• chr13-49722025-T-C
• NM_002267.4:c.656A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_002267.4(KPNA3):​c.656A>G​(p.Asn219Ser) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KPNA3 NM_002267.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 13-49722025-T-C is Pathogenic according to our data. Variant chr13-49722025-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1879259.Status of the report is criteria_provided_single_submitter, 1 stars.

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.656A>G	p.Asn219Ser	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.656A>G	p.Asn219Ser	missense	Exon 9 of 17	ENSP00000261667.3	O00505
	KPNA3	ENST00000912491.1		c.656A>G	p.Asn219Ser	missense	Exon 10 of 18	ENSP00000582550.1
	KPNA3	ENST00000950770.1		c.656A>G	p.Asn219Ser	missense	Exon 10 of 18	ENSP00000620829.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.67		Gain of catalytic residue at W222 (P = 0.0028)
MVP		0.79
MPC		1.8
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.77
Mutation Taster		=13/87	disease causing

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

Other links and lift over

hg19: chr13-50296161;