X-53234266-TG-T

Position:

• chrX-53234266-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001111125.3(IQSEC2):​c.4419del​(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

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 Pathogenic. Variant got 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 5 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 id is 599453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4419del	p.Ser1474ValfsTer21	frameshift_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4419del	p.Ser1474ValfsTer21	frameshift_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD3 exomes AF: 0.000180 AC: 9 AN: 50130 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8622

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0000556

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000279

Gnomad4 EAS exome AF: 0.0000731

Gnomad4 SAS exome AF: 0.0000325

Gnomad4 FIN exome AF: 0.0000813

Gnomad4 NFE exome AF: 0.0000132

Gnomad4 OTH exome AF: 0.0000936

GnomAD4 genome Cov.: 15

Alfa AF: 0.00102 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Feb 15, 2018	PVS1, PS2; This variant introduces a single-base-pair deletion in the coding sequence of the IQSEC2 gene, which leads to a shift in the protein reading frame and introduces of a premature termination codon in a gene where loss of function is a known mechanism of disease [ACMG: PVS1]. Sanger sequencing confirmed this to be a de novo alteration, as it was not detected in the submitted parental specimens (identity confirmed)[ACMG: PS2]. No evidence was found to support any of the ACMG Benign criteria; therefore, this alteration meets ACMG guidelines for classification as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1569290954; hg19: chrX-53263448;