chrX-53234278-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.955

Variant links:

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]

IQSEC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 14. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.4408G>A	p.Ala1470Thr	missense_variant	Exon 15 of 15	ENST00000642864.1	NP_001104595.1	Q5JU85-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1 link	c.4408G>A	p.Ala1470Thr	missense_variant	Exon 15 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.00890

AC:

780

AN:

87689

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

120

AN XY:

16295

show subpopulations

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.:

AF XY:

0.00694

AC XY:

AN XY:

8070

show subpopulations

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.:

Cov.:

AF XY:

0.0121

AC XY:

3271

AN XY:

271161

show subpopulations

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.:

Cov.:

AF XY:

0.00735

AC XY:

120

AN XY:

16325

show subpopulations

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, X-linked 1

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 26, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.98

CADD

Benign

DANN

Benign

0.97

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.61

.;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.76

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over