X-53234263-C-T

Variant names:

• chrX-53234263-C-T
• rs1242748501
• NM_001111125.3:c.4423G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001111125.3(IQSEC2):​c.4423G>A​(p.Ala1475Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 973,654 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 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: 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=0.17266929).

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.4423G>A	p.Ala1475Thr	missense	Exon 15 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001410736.1		c.*908G>A		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
	IQSEC2	NM_001441093.1		c.*908G>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.4423G>A	p.Ala1475Thr	missense	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.*908G>A		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.4582G>A	p.Ala1528Thr	missense	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 973654 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 292078

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

African (AFR) AF: 0.00 AC: 0 AN: 22101

American (AMR) AF: 0.00 AC: 0 AN: 20232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15410

East Asian (EAS) AF: 0.00 AC: 0 AN: 24498

South Asian (SAS) AF: 0.00 AC: 0 AN: 37541

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3783

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 774386

Other (OTH) AF: 0.00 AC: 0 AN: 41001

⚠️ 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.

GnomAD4 genome Cov.: 16

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	IQSEC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.049
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.027	D
Vest4		0.083
MVP		0.33
MPC		1.0
ClinPred		0.48	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.074
Mutation Taster		=95/5	polymorphism

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: rs1242748501; hg19: chrX-53263445;