rs184087864

Variant names:

• chrX-53234582-C-T
• rs184087864
• NM_001111125.3:c.4104G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-53234582-C-T
• chrX-53234582-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001111125.3(IQSEC2):​c.4104G>A​(p.Leu1368Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,118,294 control chromosomes in the GnomAD database, including 1,164 homozygotes. There are 3,431 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1368L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.067 (651 hom., 1583 hem., cov: 20)
  • Exomes 𝑓: 0.0071 (513 hom. 1848 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0530
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-53234582-C-T is Benign according to our data. Variant chrX-53234582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.4104G>A	p.Leu1368Leu	synonymous	Exon 15 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001410736.1		c.*589G>A		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
	IQSEC2	NM_001441093.1		c.*589G>A		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.4104G>A	p.Leu1368Leu	synonymous	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.*589G>A		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.4263G>A	p.Leu1421Leu	synonymous	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 7131 AN: 106704 Hom.: 653 Cov.: 20

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00536

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000890

Gnomad OTH AF: 0.0519

GnomAD2 exomes AF: 0.0221 AC: 1677 AN: 75764 AF XY: 0.0196

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00343

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00708 AC: 7164 AN: 1011557 Hom.: 513 Cov.: 34 AF XY: 0.00577 AC XY: 1848 AN XY: 320513

African (AFR) AF: 0.236 AC: 5627 AN: 23874

American (AMR) AF: 0.0142 AC: 328 AN: 23086

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 84 AN: 15556

East Asian (EAS) AF: 0.0000374 AC: 1 AN: 26727

South Asian (SAS) AF: 0.000604 AC: 26 AN: 43061

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35837

Middle Eastern (MID) AF: 0.00767 AC: 29 AN: 3779

European-Non Finnish (NFE) AF: 0.000438 AC: 349 AN: 797141

Other (OTH) AF: 0.0169 AC: 720 AN: 42496

GnomAD4 genome AF: 0.0669 AC: 7138 AN: 106737 Hom.: 651 Cov.: 20 AF XY: 0.0534 AC XY: 1583 AN XY: 29653

African (AFR) AF: 0.235 AC: 6789 AN: 28852

American (AMR) AF: 0.0212 AC: 213 AN: 10060

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 14 AN: 2610

East Asian (EAS) AF: 0.00 AC: 0 AN: 3370

South Asian (SAS) AF: 0.000831 AC: 2 AN: 2406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.000890 AC: 46 AN: 51663

Other (OTH) AF: 0.0513 AC: 74 AN: 1442

Alfa AF: 0.112 Hom.: 1529

Bravo AF: 0.0786

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		-0.053
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs184087864; hg19: chrX-53263764; COSMIC: COSV64723217; COSMIC: COSV64723217;