rs191886831

chrX-53234278-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111125.3(IQSEC2):c.4408G>A(p.Ala1470Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,026,508 control chromosomes in the GnomAD database, including 76 homozygotes. There are 3,391 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (10 hom., 120 hem., cov: 14)
  • Exomes 𝑓: 0.012 (66 hom. 3271 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.955

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029886663).
• BP6: Variant X-53234278-C-T is Benign according to our data. Variant chrX-53234278-C-T is described in ClinVar as [Benign]. Clinvar id is 129284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53234278-C-T is described in Lovd as [Benign]. Variant chrX-53234278-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00888 (779/87713) while in subpopulation NFE AF= 0.0122 (548/44756). AF 95% confidence interval is 0.0114. There are 10 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4408G>A	p.Ala1470Thr	missense_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4408G>A	p.Ala1470Thr	missense_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 780 AN: 87689 Hom.: 10 Cov.: 14 AF XY: 0.00736 AC XY: 120 AN XY: 16295

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.00795

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000374

Gnomad SAS AF: 0.000646

Gnomad FIN AF: 0.00629

Gnomad MID AF: 0.00493

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00536

GnomAD3 exomes AF: 0.00682 AC: 344 AN: 50460 Hom.: 2 AF XY: 0.00694 AC XY: 56 AN XY: 8070

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000880

Gnomad FIN exome AF: 0.00626

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.0123 AC: 11513 AN: 938795 Hom.: 66 Cov.: 21 AF XY: 0.0121 AC XY: 3271 AN XY: 271161

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.0000845

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00847

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00888 AC: 779 AN: 87713 Hom.: 10 Cov.: 14 AF XY: 0.00735 AC XY: 120 AN XY: 16325

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00794

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000376

Gnomad4 SAS AF: 0.000650

Gnomad4 FIN AF: 0.00629

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00528

Alfa AF: 0.0121 Hom.: 190

ExAC AF: 0.00593 AC: 120

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Intellectual disability, X-linked 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.98
Cadd	Benign	18
Dann	Benign	0.97
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.71	N;.
REVEL	Benign	0.028
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.67	T;.
Vest4		0.032
MVP		0.082
MPC		1.0
ClinPred		0.0048	T
GERP RS		2.3
Varity_R		0.090
gMVP		0.089

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: rs191886831; hg19: chrX-53263460; COSMIC: COSV64724676; COSMIC: COSV64724676;