chr3-122461283-G-A

Variant names:

• chr3-122461283-G-A
• rs2076321019
• NM_002264.4:c.373C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002264.4(KPNA1):​c.373C>T​(p.Pro125Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KPNA1 NM_002264.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

Genes affected

KPNA1 (HGNC:6394): (karyopherin subunit alpha 1) 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. This protein interacts with the recombination activating gene 1 (RAG1) protein and is a putative substrate of the RAG1 ubiquitin ligase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31282538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA1	NM_002264.4	c.373C>T	p.Pro125Ser	missense_variant	Exon 5 of 14	ENST00000344337.11	NP_002255.3
KPNA1	XM_005247437.5	c.373C>T	p.Pro125Ser	missense_variant	Exon 5 of 14		XP_005247494.1
KPNA1	XM_024453514.2	c.373C>T	p.Pro125Ser	missense_variant	Exon 5 of 14		XP_024309282.1
KPNA1	NR_026698.2	n.561C>T		non_coding_transcript_exon_variant	Exon 5 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA1	ENST00000344337.11	c.373C>T	p.Pro125Ser	missense_variant	Exon 5 of 14	1	NM_002264.4	ENSP00000343701.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373C>T (p.P125S) alteration is located in exon 5 (coding exon 4) of the KPNA1 gene. This alteration results from a C to T substitution at nucleotide position 373, causing the proline (P) at amino acid position 125 to be replaced by a serine (S). 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	Benign	0.12
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;T;T
Eigen	Benign	0.055
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.39	N;.;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.080	T;D;D;D;D
Sift4G	Benign	0.36	T;.;.;D;.
Polyphen		0.0010	B;.;.;.;.
Vest4		0.17
MutPred		0.48		Gain of glycosylation at P125 (P = 0.0103);Gain of glycosylation at P125 (P = 0.0103);Gain of glycosylation at P125 (P = 0.0103);Gain of glycosylation at P125 (P = 0.0103);Gain of glycosylation at P125 (P = 0.0103);
MVP		0.41
MPC		0.90
ClinPred		0.90	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.31
Mutation Taster		=77/23	polymorphism

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: rs2076321019; hg19: chr3-122180130;