chrX-53234227-C-T

Position:

• chrX-53234227-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001111125.3(IQSEC2):​c.4459G>A​(p.Val1487Met) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000063 (0 hom. 2 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.42

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21743616).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4459G>A	p.Val1487Met	missense_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4459G>A	p.Val1487Met	missense_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD3 exomes AF: 0.0000156 AC: 1 AN: 64213 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000922

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000634 AC: 6 AN: 946927 Hom.: 0 Cov.: 18 AF XY: 0.00000726 AC XY: 2 AN XY: 275315

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: 0.0000872

Gnomad4 NFE exome AF: 0.00000133

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome Cov.: 17

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2021	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. 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. ClinVar contains an entry for this variant (Variation ID: 423803). This missense change has been observed in individual(s) with clinical features of X-linked intellectual disability (Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces valine with methionine at codon 1487 of the IQSEC2 protein (p.Val1487Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jan 25, 2021	The p.Val1487Met variant in the IQSEC2 gene has not been previously reported in association with disease. This variant has been identified in 1/10,846 Finnish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The IQSEC2 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. The p.Val1487Met variant is located in the PDZ binding motif of IQSEC2. While this domain is not currently an established critical domain, some evidence suggests it may be necessary for interaction with PDZ proteins, which are required for the function of the protein at the synapse (Mignot et al., 2019). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Val1487Met variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP2] -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2017

A variant of uncertain significance has been identified in the IQSEC2 gene. The V1487M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1487M variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the V1487M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0060	D;.
Vest4		0.32
MutPred		0.17		Loss of glycosylation at S1485 (P = 0.1192);Loss of glycosylation at S1485 (P = 0.1192);
MVP		0.30
MPC		1.1
ClinPred		0.73	D
GERP RS		3.1
Varity_R		0.39
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1064796639; hg19: chrX-53263409; COSMIC: COSV100945172; COSMIC: COSV100945172;