12-125703-G-A

Variant names:

• chr12-125703-G-A
• rs782459662
• NM_001170738.2:c.694G>A

Variant summary

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

The NM_001170738.2(IQSEC3):​c.694G>A​(p.Gly232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,534,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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: 0.000013 (0 hom.)
• Consequence: IQSEC3 NM_001170738.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

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]

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=0.22868332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.694G>A	p.Gly232Ser	missense_variant	Exon 3 of 14	ENST00000538872.6	NP_001164209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6	c.694G>A	p.Gly232Ser	missense_variant	Exon 3 of 14	5	NM_001170738.2	ENSP00000437554.1
IQSEC3	ENST00000382841.2	c.-6-12564G>A		intron_variant	Intron 2 of 12	2		ENSP00000372292.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000203 AC: 3 AN: 147968 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 18 AN: 1381914 Hom.: 0 Cov.: 30 AF XY: 0.0000117 AC XY: 8 AN XY: 682972

African (AFR) AF: 0.0000663 AC: 2 AN: 30164

American (AMR) AF: 0.000113 AC: 4 AN: 35480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22506

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37266

South Asian (SAS) AF: 0.00 AC: 0 AN: 75496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00000646 AC: 7 AN: 1083268

Other (OTH) AF: 0.0000174 AC: 1 AN: 57484

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15282

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: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.694G>A (p.G232S) 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 694, causing the glycine (G) at amino acid position 232 to be replaced by a serine (S). 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	0.090
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0098	T
Eigen	Benign	0.047
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.18
Sift	Benign	0.13	T
Sift4G	Benign	0.43	T
Vest4		0.11
MutPred		0.19		Gain of glycosylation at G232 (P = 0.0017);
MVP		0.71
MPC		0.45
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.23
Mutation Taster		=93/7	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: rs782459662; hg19: chr12-234869;