NM_001111125.3:c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT

Variant names:

• chrX-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT
• rs1556880284
• NM_001111125.3:c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001111125.3(IQSEC2):​c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT​(p.Ala19IlefsTer32) variant causes a frameshift, synonymous change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: IQSEC2 NM_001111125.3 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.988 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT is Pathogenic according to our data. Variant chrX-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT is described in ClinVar as [Pathogenic]. Clinvar id is 545445.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT	p.Ala19IlefsTer32	frameshift_variant, synonymous_variant	Exon 1 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT	p.Ala19IlefsTer32	frameshift_variant, synonymous_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:1

Feb 15, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556880284; hg19: chrX-53350171;