NM_001366306.2:c.42G>A

Variant names:

• chr6-116689357-G-A
• rs369865783
• NM_001366306.2:c.42G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001366306.2(KPNA5):​c.42G>A​(p.Met14Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,608,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M14L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: KPNA5 NM_001366306.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.45
• Publications: 0 publications found

Genes affected

KPNA5 (HGNC:6398): (karyopherin subunit alpha 5) 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 and is probably 120 million daltons in molecular size. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion; larger molecules are transported by an active process. Most nuclear proteins contain short basic amino acid sequences known as nuclear localization signals (NLSs). KPNA5 protein belongs to the importin alpha protein family and is thought to be involved in NLS-dependent protein import into the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15706408).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366306.2. 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
	KPNA5	NM_001366306.2	MANE Select	c.42G>A	p.Met14Ile	missense	Exon 2 of 14	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.102G>A	p.Met34Ile	missense	Exon 3 of 16	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.102G>A	p.Met34Ile	missense	Exon 3 of 15	NP_001353234.1	A0A8V8TMV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA5	ENST00000368564.7	TSL:1 MANE Select	c.42G>A	p.Met14Ile	missense	Exon 2 of 14	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.42G>A	p.Met14Ile	missense	Exon 2 of 15	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.42G>A	p.Met14Ile	missense	Exon 2 of 15	ENSP00000607557.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000488 AC: 12 AN: 245900 AF XY: 0.0000526

Gnomad AFR exome AF: 0.0000624

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: 0.0000980

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 160 AN: 1456214 Hom.: 0 Cov.: 30 AF XY: 0.0000994 AC XY: 72 AN XY: 724448

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 43158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 85108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000142 AC: 158 AN: 1110260

Other (OTH) AF: 0.0000332 AC: 2 AN: 60152

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74288

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67998

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

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.055
Sift	Benign	0.23	T
Sift4G	Benign	0.33	T
Vest4		0.48
MutPred		0.43		Loss of helix (P = 0.0626)
MVP		0.25
MPC		0.91
ClinPred		0.24	T
GERP RS		4.5
gMVP		0.41
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: rs369865783; hg19: chr6-117010520;