rs781957490

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001170738.2(IQSEC3):​c.653G>A​(p.Gly218Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,534,468 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

Publications

0 publications found
Variant links:
Genes affected
IQSEC3 (HGNC:29193): (IQ motif and Sec7 domain ArfGEF 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including actin cytoskeleton organization; activation of GTPase activity; and regulation of small GTPase mediated signal transduction. Located in cytosol and nucleoplasm. [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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.169675).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IQSEC3NM_001170738.2 linkc.653G>A p.Gly218Asp missense_variant Exon 3 of 14 ENST00000538872.6 NP_001164209.1 Q9UPP2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IQSEC3ENST00000538872.6 linkc.653G>A p.Gly218Asp missense_variant Exon 3 of 14 5 NM_001170738.2 ENSP00000437554.1 Q9UPP2-1
IQSEC3ENST00000382841.2 linkc.-6-12605G>A intron_variant Intron 2 of 12 2 ENSP00000372292.2 Q9UPP2-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD2 exomes
AF:
0.0000121
AC:
2
AN:
164868
AF XY:
0.0000110
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000391
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000125
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000145
AC:
2
AN:
1382226
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
683220
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
29648
American (AMR)
AF:
0.0000283
AC:
1
AN:
35320
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21612
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37770
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74766
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
35592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5470
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1084506
Other (OTH)
AF:
0.0000174
AC:
1
AN:
57542
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.600
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74382
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41464
American (AMR)
AF:
0.0000654
AC:
1
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), 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

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:
0.00000378
ExAC
AF:
0.0000256
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 20, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.653G>A (p.G218D) alteration is located in exon 3 (coding exon 3) of the IQSEC3 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the glycine (G) at amino acid position 218 to be replaced by an aspartic acid (D). 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
0.14
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.011
T
Eigen
Benign
0.097
Eigen_PC
Benign
0.22
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.70
T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
L
PhyloP100
2.3
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.68
N
REVEL
Benign
0.097
Sift
Benign
0.19
T
Sift4G
Benign
0.097
T
Vest4
0.41
MutPred
0.20
Gain of catalytic residue at V223 (P = 0.0014);
MVP
0.39
MPC
1.2
ClinPred
0.36
T
GERP RS
4.5
Varity_R
0.18
gMVP
0.24
Mutation Taster
=88/12
polymorphism

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: rs781957490; hg19: chr12-234828; API