chrX-53234278-C-T

Position:

chrX-53234278-C-T

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/exons	MANE	UniProt
IQSEC2	NM_001111125.3 linkuse as main transcript	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 linkuse as main transcript	c.4408G>A	p.Ala1470Thr	missense_variant	15/15		NM_001111125.3	P1	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

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -

Intellectual disability, X-linked 1

Benign:2

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

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

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

MutationTaster

Benign

1.0

N;N;N

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