NM_001111125.3:c.4448G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001111125.3(IQSEC2):c.4448G>A(p.Arg1483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000103 in 972,541 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 17)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.05

Publications

0 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), Ambry Genetics, G2P
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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.260886).

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	UniProt
IQSEC2	NM_001111125.3	MANE Select	c.4448G>A	p.Arg1483Gln	missense	Exon 15 of 15	NP_001104595.1	Q5JU85-2
IQSEC2	NM_001410736.1		c.*933G>A		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
IQSEC2	NM_001441093.1		c.*933G>A		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC2	ENST00000642864.1	MANE Select	c.4448G>A	p.Arg1483Gln	missense	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
IQSEC2	ENST00000375365.2	TSL:1	c.*933G>A		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
IQSEC2	ENST00000706952.1		c.4607G>A	p.Arg1536Gln	missense	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

98193

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000103

AC:

AN:

972541

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

291157

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22270

American (AMR)

AF:

0.00

AC:

AN:

21081

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15494

East Asian (EAS)

AF:

0.00

AC:

AN:

24376

South Asian (SAS)

AF:

0.00

AC:

AN:

38591

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34497

Middle Eastern (MID)

AF:

0.000265

AC:

AN:

3770

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771541

Other (OTH)

AF:

0.00

AC:

AN:

40921

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

98193

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22435

African (AFR)

AF:

0.00

AC:

AN:

26499

American (AMR)

AF:

0.00

AC:

AN:

8901

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2454

East Asian (EAS)

AF:

0.00

AC:

AN:

3004

South Asian (SAS)

AF:

0.00

AC:

AN:

1870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4393

Middle Eastern (MID)

AF:

0.00

AC:

AN:

228

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

48947

Other (OTH)

AF:

0.00

AC:

AN:

1283

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, X-linked 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

PhyloP100

6.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.038

Vest4

0.30

MVP

0.30

MPC

1.2

ClinPred

0.90

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.15

Mutation Taster

=89/11

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over