X-53234268-G-C

Variant names:

• chrX-53234268-G-C
• rs1556858927
• NM_001111125.3:c.4418C>G

Variant summary

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

The NM_001111125.3(IQSEC2):​c.4418C>G​(p.Pro1473Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000102 in 975,904 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts 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. P1473L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

IQSEC2 (HGNC:29059): (IQ motif and Sec7 domain ArfGEF 2) This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

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=0.2325353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.4418C>G	p.Pro1473Arg	missense_variant	Exon 15 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4418C>G	p.Pro1473Arg	missense_variant	Exon 15 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 975904 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 294814

⚠️ 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: 22074

American (AMR) AF: 0.00 AC: 0 AN: 20090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15432

East Asian (EAS) AF: 0.00 AC: 0 AN: 24474

South Asian (SAS) AF: 0.00 AC: 0 AN: 38361

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3782

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 775789

Other (OTH) AF: 0.00 AC: 0 AN: 41094

⚠️ 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.

GnomAD4 genome Cov.: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Uncertain:1

Mar 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1473 of the IQSEC2 protein (p.Pro1473Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IQSEC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Uncertain	23
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.95	T
PhyloP100		3.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.71	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.27	T;.
Vest4		0.17
MutPred		0.35		Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);
MVP		0.19
MPC		1.1
ClinPred		0.57	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.19
Mutation Taster		=91/9	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

Publications

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Other links and lift over

dbSNP: rs1556858927; hg19: chrX-53263450;