NM_001111125.3:c.708-3C>T

Variant names:

• chrX-53291927-G-A
• rs781873807
• NM_001111125.3:c.708-3C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001111125.3(IQSEC2):​c.708-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,164,030 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: IQSEC2 NM_001111125.3 splice_region, intron
• Scores: Splicing: ADA: 0.01065
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.42
• 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), 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.708-3C>T		splice_region intron	N/A	NP_001104595.1
	IQSEC2	NM_001441092.1		c.708-3C>T		splice_region intron	N/A	NP_001428021.1
	IQSEC2	NM_001410736.1		c.708-3C>T		splice_region intron	N/A	NP_001397665.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.708-3C>T		splice_region intron	N/A	ENSP00000495726.1
	IQSEC2	ENST00000706952.1		c.867-3C>T		splice_region intron	N/A	ENSP00000516672.1
	IQSEC2	ENST00000674510.1		c.708-3C>T		splice_region intron	N/A	ENSP00000502054.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111852 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000175 AC: 2 AN: 114265 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 13 AN: 1052127 Hom.: 0 Cov.: 28 AF XY: 0.00000875 AC XY: 3 AN XY: 342977

African (AFR) AF: 0.00 AC: 0 AN: 24877

American (AMR) AF: 0.00 AC: 0 AN: 27884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18607

East Asian (EAS) AF: 0.00 AC: 0 AN: 27109

South Asian (SAS) AF: 0.00 AC: 0 AN: 49741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37621

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4081

European-Non Finnish (NFE) AF: 0.00000978 AC: 8 AN: 817894

Other (OTH) AF: 0.000113 AC: 5 AN: 44313

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111903 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34089

African (AFR) AF: 0.00 AC: 0 AN: 30862

American (AMR) AF: 0.00 AC: 0 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53113

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, X-linked 1 (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		2.4
PromoterAI		-0.026	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.070

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

Other links and lift over

dbSNP: rs781873807; hg19: chrX-53321109;