X-53234372-T-G

Variant names:

• chrX-53234372-T-G
• rs587780360
• NM_001111125.3:c.4314A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001111125.3(IQSEC2):​c.4314A>C​(p.Pro1438Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.0034 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.280
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.4314A>C	p.Pro1438Pro	synonymous_variant	Exon 15 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4314A>C	p.Pro1438Pro	synonymous_variant	Exon 15 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 54 AN: 8069 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00382

Gnomad ASJ AF: 0.00840

Gnomad EAS AF: 0.00599

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00616 AC: 33 AN: 5354 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00340 AC: 392 AN: 115345 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 20029

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

African (AFR) AF: 0.00216 AC: 5 AN: 2314

American (AMR) AF: 0.0182 AC: 21 AN: 1155

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 6 AN: 1094

East Asian (EAS) AF: 0.00376 AC: 6 AN: 1597

South Asian (SAS) AF: 0.00759 AC: 31 AN: 4082

European-Finnish (FIN) AF: 0.00398 AC: 20 AN: 5028

Middle Eastern (MID) AF: 0.0132 AC: 3 AN: 228

European-Non Finnish (NFE) AF: 0.00283 AC: 270 AN: 95504

Other (OTH) AF: 0.00691 AC: 30 AN: 4343

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00669 AC: 54 AN: 8072 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 682

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

African (AFR) AF: 0.00617 AC: 11 AN: 1783

American (AMR) AF: 0.00382 AC: 2 AN: 524

Ashkenazi Jewish (ASJ) AF: 0.00840 AC: 2 AN: 238

East Asian (EAS) AF: 0.00592 AC: 1 AN: 169

South Asian (SAS) AF: 0.00 AC: 0 AN: 57

European-Finnish (FIN) AF: 0.00292 AC: 1 AN: 342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00772 AC: 37 AN: 4791

Other (OTH) AF: 0.00 AC: 0 AN: 92

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0253 Hom.: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Feb 06, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 12, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.92
DANN	Benign	0.44
PhyloP100		-0.28

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: rs587780360; hg19: chrX-53263554;