X-53320689-G-A

Position:

• chrX-53320689-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001111125.3(IQSEC2):​c.435C>T​(p.Thr145Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,165,643 control chromosomes in the GnomAD database, including 6 homozygotes. There are 489 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (6 hom. 463 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.407

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-53320689-G-A is Benign according to our data. Variant chrX-53320689-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 382937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53320689-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.407 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.435C>T	p.Thr145Thr	synonymous_variant	1/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.435C>T	p.Thr145Thr	synonymous_variant	1/15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 109 AN: 112822 Hom.: 0 Cov.: 23 AF XY: 0.000743 AC XY: 26 AN XY: 35012

Gnomad AFR AF: 0.000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000737

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00130

GnomAD3 exomes AF: 0.000963 AC: 103 AN: 106981 Hom.: 0 AF XY: 0.000910 AC XY: 35 AN XY: 38449

Gnomad AFR exome AF: 0.000169

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000861

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.00140 AC: 1470 AN: 1052768 Hom.: 6 Cov.: 32 AF XY: 0.00135 AC XY: 463 AN XY: 344080

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.000753

Gnomad4 ASJ exome AF: 0.0000537

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000401

Gnomad4 FIN exome AF: 0.000510

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.000881

GnomAD4 genome AF: 0.000966 AC: 109 AN: 112875 Hom.: 0 Cov.: 23 AF XY: 0.000741 AC XY: 26 AN XY: 35075

Gnomad4 AFR AF: 0.000256

Gnomad4 AMR AF: 0.000736

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.000763 Hom.: 4

Bravo AF: 0.00104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	GeneDx	Nov 25, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -

Intellectual disability, X-linked 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2016

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.9
DANN	Benign	0.95

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782726368; hg19: chrX-53349887;