X-53234221-A-T

Position:

• chrX-53234221-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_001111125.3(IQSEC2):​c.4465T>A​(p.Ter1489ArgextTer1) variant causes a stop lost change. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.11

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 Uncertain_significance. Variant got 4 ACMG points.

• PM4: Stoplost variant in NM_001111125.3 Downstream stopcodon found after 321 codons.
• PP5: Variant X-53234221-A-T is Pathogenic according to our data. Variant chrX-53234221-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1310781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4465T>A	p.Ter1489ArgextTer1	stop_lost	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4465T>A	p.Ter1489ArgextTer1	stop_lost	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 913738 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 257554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 18

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Stop codon loss and change to an arginine codon, leading to protein extension and the addition of 1 amino acids at the C-terminus; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.88
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;N;N
Vest4		0.022
GERP RS		3.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-53263403;