rs1556859040

Variant names:

• chrX-53234533-G-A
• rs1556859040
• NM_001111125.3:c.4153C>T

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.4153C>T​(p.Pro1385Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 996,299 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1385P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000040 (0 hom. 1 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.35
• 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), 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

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=0.20706004).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.4153C>T	p.Pro1385Ser	missense	Exon 15 of 15	NP_001104595.1
	IQSEC2	NM_001410736.1		c.*638C>T		3_prime_UTR	Exon 14 of 14	NP_001397665.1
	IQSEC2	NM_001441093.1		c.*638C>T		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.4153C>T	p.Pro1385Ser	missense	Exon 15 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.*638C>T		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.4312C>T	p.Pro1438Ser	missense	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000401 AC: 4 AN: 996299 Hom.: 0 Cov.: 33 AF XY: 0.00000320 AC XY: 1 AN XY: 312259

African (AFR) AF: 0.00 AC: 0 AN: 23301

American (AMR) AF: 0.00 AC: 0 AN: 20644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14967

East Asian (EAS) AF: 0.00 AC: 0 AN: 26313

South Asian (SAS) AF: 0.00 AC: 0 AN: 40584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35311

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3741

European-Non Finnish (NFE) AF: 0.00000507 AC: 4 AN: 789544

Other (OTH) AF: 0.00 AC: 0 AN: 41894

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 10, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1385S variant (also known as c.4153C>T), located in coding exon 15 of the IQSEC2 gene, results from a C to T substitution at nucleotide position 4153. The proline at codon 1385 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Intellectual disability, X-linked 1 Uncertain:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1385 of the IQSEC2 protein (p.Pro1385Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 471272). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IQSEC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.048
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.22	T
Vest4		0.38
MutPred		0.24		Loss of ubiquitination at K1386 (P = 0.1465)
MVP		0.20
MPC		2.1
ClinPred		0.47	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.047
Mutation Taster		=96/4	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: rs1556859040; hg19: chrX-53263715;