rs781909069

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001170738.2(IQSEC3):​c.707C>G​(p.Ala236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,382,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A236V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

2
3
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14538032).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IQSEC3NM_001170738.2 linkc.707C>G p.Ala236Gly 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.707C>G p.Ala236Gly missense_variant Exon 3 of 14 5 NM_001170738.2 ENSP00000437554.1 Q9UPP2-1
IQSEC3ENST00000382841.2 linkc.-6-12551C>G intron_variant Intron 2 of 12 2 ENSP00000372292.2 Q9UPP2-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.24e-7
AC:
1
AN:
1382006
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
682812
show subpopulations
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:
9.24e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.014
T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.062
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.63
T
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
0.81
L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.10
N
REVEL
Benign
0.17
Sift
Uncertain
0.025
D
Sift4G
Benign
0.38
T
Vest4
0.22
MutPred
0.21
Gain of catalytic residue at A236 (P = 0.0011);
MVP
0.58
MPC
0.47
ClinPred
0.23
T
GERP RS
3.5
Varity_R
0.044
gMVP
0.17

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-234882; API