Genetic Variant NM_001111125.3:c.4408G>A (chrX-53234278-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 12/19 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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
intellectual disability, X-linked 1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

IQSEC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 14. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	NM_001111125.3	MANE Select	c.4408G>A	p.Ala1470Thr	missense	Exon 15 of 15	NP_001104595.1
IQSEC2	NM_001410736.1		c.*893G>A		3_prime_UTR	Exon 14 of 14	NP_001397665.1
IQSEC2	NM_001441093.1		c.*893G>A		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	ENST00000642864.1	MANE Select	c.4408G>A	p.Ala1470Thr	missense	Exon 15 of 15	ENSP00000495726.1
IQSEC2	ENST00000375365.2	TSL:1	c.*893G>A		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
IQSEC2	ENST00000706952.1		c.4567G>A	p.Ala1523Thr	missense	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes

AF:

0.00890

AC:

780

AN:

87689

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00682

AC:

344

AN:

50460

AF XY:

0.00694

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 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

African (AFR)

AF:

0.00146

AC:

AN:

21177

American (AMR)

AF:

0.00429

AC:

AN:

17936

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

200

AN:

14474

East Asian (EAS)

AF:

0.0000845

AC:

AN:

23675

South Asian (SAS)

AF:

0.00138

AC:

AN:

33966

European-Finnish (FIN)

AF:

0.00847

AC:

284

AN:

33529

Middle Eastern (MID)

AF:

0.00631

AC:

AN:

3646

European-Non Finnish (NFE)

AF:

0.0139

AC:

10453

AN:

750938

Other (OTH)

AF:

0.0100

AC:

396

AN:

39454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

347

693

1040

1386

1733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00888

AC:

779

AN:

87713

Hom.:

Cov.:

AF XY:

0.00735

AC XY:

120

AN XY:

16325

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

23281

American (AMR)

AF:

0.00794

AC:

AN:

7686

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

2289

East Asian (EAS)

AF:

0.000376

AC:

AN:

2661

South Asian (SAS)

AF:

0.000650

AC:

AN:

1538

European-Finnish (FIN)

AF:

0.00629

AC:

AN:

3658

Middle Eastern (MID)

AF:

0.00546

AC:

AN:

183

European-Non Finnish (NFE)

AF:

0.0122

AC:

548

AN:

44756

Other (OTH)

AF:

0.00528

AC:

AN:

1136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not specified

Benign:4

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

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.

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability, X-linked 1

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.98

CADD

Benign

(source)

DANN

Benign

0.97

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.0

PhyloP100

0.95

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.71

REVEL

Benign

0.028

Sift

Uncertain

0.0070

Sift4G

Benign

0.67

Vest4

0.032

MVP

0.082

MPC

1.0

ClinPred

0.0048

GERP RS

2.3

Varity_R

0.090

gMVP

0.089

Mutation Taster

=100/0

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over