NM_001111125.3:c.4419delC

Variant names:

• chrX-53234266-TG-T
• rs1569290954
• NM_001111125.3:c.4419delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001111125.3(IQSEC2):​c.4419delC​(p.Ser1474ValfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 829,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1473P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.000027 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.16
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PP5: Variant X-53234266-TG-T is Pathogenic according to our data. Variant chrX-53234266-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 599453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4419delC	p.Ser1474ValfsTer21	frameshift	Exon 15 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001410736.1		c.*904delC		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
	IQSEC2	NM_001441093.1		c.*904delC		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.4419delC	p.Ser1474ValfsTer21	frameshift	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.*904delC		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.4578delC	p.Ser1527ValfsTer21	frameshift	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD2 exomes AF: 0.000180 AC: 9 AN: 50130 AF XY: 0.00

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000847

Gnomad EAS exome AF: 0.000329

Gnomad FIN exome AF: 0.0000974

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000265 AC: 22 AN: 829857 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 235173

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

African (AFR) AF: 0.0000556 AC: 1 AN: 17977

American (AMR) AF: 0.000134 AC: 2 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.000279 AC: 3 AN: 10751

East Asian (EAS) AF: 0.0000731 AC: 1 AN: 13671

South Asian (SAS) AF: 0.0000325 AC: 1 AN: 30744

European-Finnish (FIN) AF: 0.0000813 AC: 2 AN: 24596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3115

European-Non Finnish (NFE) AF: 0.0000132 AC: 9 AN: 682018

Other (OTH) AF: 0.0000936 AC: 3 AN: 32053

⚠️ 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.: 15

Alfa AF: 0.00102 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, X-linked 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs1569290954; hg19: chrX-53263448; COSMIC: COSV64724078; COSMIC: COSV64724078;