GeneBe

6-10703451-A-G

Variant names:

Variant summary

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

The NM_017906.3(PAK1IP1):​c.490A>G​(p.Lys164Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,603,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PAK1IP1
NM_017906.3 missense

Scores

5
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.16

Publications

0 publications found
Variant links:
Genes affected
PAK1IP1 (HGNC:20882): (PAK1 interacting protein 1) Involved in regulation of signal transduction by p53 class mediator and ribosomal large subunit biogenesis. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
PAK1IP1NM_017906.3 linkc.490A>G p.Lys164Glu missense_variant Exon 5 of 10 ENST00000379568.4 NP_060376.2 Q9NWT1A0A0S2Z5C3
PAK1IP1XM_011514721.1 linkc.556A>G p.Lys186Glu missense_variant Exon 6 of 11 XP_011513023.1
PAK1IP1XM_005249204.3 linkc.493A>G p.Lys165Glu missense_variant Exon 5 of 10 XP_005249261.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAK1IP1ENST00000379568.4 linkc.490A>G p.Lys164Glu missense_variant Exon 5 of 10 1 NM_017906.3 ENSP00000368887.3 Q9NWT1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1450806
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
722286
show subpopulations
⚠️ 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:
33272
American (AMR)
AF:
0.00
AC:
0
AN:
44434
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26040
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39572
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85460
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5610
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1103054
Other (OTH)
AF:
0.0000167
AC:
1
AN:
59976
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41458
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.542
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 21, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.490A>G (p.K164E) alteration is located in exon 5 (coding exon 5) of the PAK1IP1 gene. This alteration results from a A to G substitution at nucleotide position 490, causing the lysine (K) at amino acid position 164 to be replaced by a glutamic acid (E). 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
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.16
T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.73
D
MetaSVM
Benign
-0.98
T
MutationAssessor
Pathogenic
3.2
M
PhyloP100
8.2
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.1
D
REVEL
Benign
0.26
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.046
D
Polyphen
0.61
P
Vest4
0.75
MutPred
0.48
Loss of MoRF binding (P = 0.0065);
MVP
0.55
MPC
0.74
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.58
gMVP
0.62
Mutation Taster
=45/55
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1305414182; hg19: chr6-10703684; API