3-122449719-C-A

Variant names:

• chr3-122449719-C-A
• rs996436531
• NM_002264.4:c.772G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002264.4(KPNA1):​c.772G>T​(p.Val258Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KPNA1 NM_002264.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA1	NM_002264.4	c.772G>T	p.Val258Leu	missense_variant	Exon 9 of 14	ENST00000344337.11	NP_002255.3
KPNA1	XM_005247437.5	c.772G>T	p.Val258Leu	missense_variant	Exon 9 of 14		XP_005247494.1
KPNA1	XM_024453514.2	c.772G>T	p.Val258Leu	missense_variant	Exon 9 of 14		XP_024309282.1
KPNA1	NR_026698.2	n.1083G>T		non_coding_transcript_exon_variant	Exon 10 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA1	ENST00000344337.11	c.772G>T	p.Val258Leu	missense_variant	Exon 9 of 14	1	NM_002264.4	ENSP00000343701.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458902 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725758

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.772G>T (p.V258L) alteration is located in exon 9 (coding exon 8) of the KPNA1 gene. This alteration results from a G to T substitution at nucleotide position 772, causing the valine (V) at amino acid position 258 to be replaced by a leucine (L). 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	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Benign	0.14	T;T
Sift4G	Benign	0.16	T;.
Polyphen		0.046	B;.
Vest4		0.65
MutPred		0.55		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.87
MPC		1.2
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs996436531; hg19: chr3-122168566;