3-122467335-A-G

Variant names:

• chr3-122467335-A-G
• rs1278219654
• NM_002264.4:c.224T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002264.4(KPNA1):​c.224T>C​(p.Met75Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000128 in 1,560,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KPNA1 NM_002264.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1797665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA1	NM_002264.4	c.224T>C	p.Met75Thr	missense_variant	Exon 3 of 14	ENST00000344337.11	NP_002255.3
KPNA1	XM_005247437.5	c.224T>C	p.Met75Thr	missense_variant	Exon 3 of 14		XP_005247494.1
KPNA1	XM_024453514.2	c.224T>C	p.Met75Thr	missense_variant	Exon 3 of 14		XP_024309282.1
KPNA1	NR_026698.2	n.412T>C		non_coding_transcript_exon_variant	Exon 3 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA1	ENST00000344337.11	c.224T>C	p.Met75Thr	missense_variant	Exon 3 of 14	1	NM_002264.4	ENSP00000343701.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408102 Hom.: 0 Cov.: 20 AF XY: 0.00000142 AC XY: 1 AN XY: 703574

⚠️ 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: 32404

American (AMR) AF: 0.00 AC: 0 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 84522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1065294

Other (OTH) AF: 0.00 AC: 0 AN: 58468

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000565 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224T>C (p.M75T) alteration is located in exon 3 (coding exon 2) of the KPNA1 gene. This alteration results from a T to C substitution at nucleotide position 224, causing the methionine (M) at amino acid position 75 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.75
DEOGEN2	Benign	0.088	T;.;.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.57	T;T;T;T;T
Sift4G	Benign	0.63	T;.;.;T;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.47
MutPred		0.37		Gain of glycosylation at M75 (P = 0.0435);Gain of glycosylation at M75 (P = 0.0435);Gain of glycosylation at M75 (P = 0.0435);Gain of glycosylation at M75 (P = 0.0435);Gain of glycosylation at M75 (P = 0.0435);
MVP		0.92
MPC		1.0
ClinPred		0.70	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.51
Mutation Taster		=59/41	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: rs1278219654; hg19: chr3-122186182;