NM_001111125.3:c.4391C>G

Variant names:

• chrX-53234295-G-C
• rs1556858946
• NM_001111125.3:c.4391C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001111125.3(IQSEC2):​c.4391C>G​(p.Ser1464Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1464P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000012 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25574932).

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.4391C>G	p.Ser1464Cys	missense	Exon 15 of 15	NP_001104595.1
	IQSEC2	NM_001410736.1		c.*876C>G		3_prime_UTR	Exon 14 of 14	NP_001397665.1
	IQSEC2	NM_001441093.1		c.*876C>G		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.4391C>G	p.Ser1464Cys	missense	Exon 15 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.*876C>G		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.4550C>G	p.Ser1517Cys	missense	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 846311 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 207229

African (AFR) AF: 0.00 AC: 0 AN: 19000

American (AMR) AF: 0.00 AC: 0 AN: 14739

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12648

East Asian (EAS) AF: 0.00 AC: 0 AN: 22047

South Asian (SAS) AF: 0.00 AC: 0 AN: 32281

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3360

European-Non Finnish (NFE) AF: 0.00000148 AC: 1 AN: 674508

Other (OTH) AF: 0.00 AC: 0 AN: 35926

GnomAD4 genome Cov.: 13

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.10	T
Vest4		0.17
MutPred		0.19		Loss of glycosylation at S1464 (P = 2e-04)
MVP		0.30
MPC		1.0
ClinPred		0.67	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.13
Mutation Taster		=74/26	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: rs1556858946; hg19: chrX-53263477;