NM_001111125.3:c.3735C>T

Variant names:

• chrX-53234951-G-A
• rs797045630
• NM_001111125.3:c.3735C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001111125.3(IQSEC2):​c.3735C>T​(p.His1245His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,129,052 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 4 hem., cov: 21)
  • Exomes 𝑓: 0.00021 (0 hom. 87 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.08
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-53234951-G-A is Benign according to our data. Variant chrX-53234951-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211207.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.3735C>T	p.His1245His	synonymous	Exon 15 of 15	NP_001104595.1
	IQSEC2	NM_001410736.1		c.*220C>T		3_prime_UTR	Exon 14 of 14	NP_001397665.1
	IQSEC2	NM_001441093.1		c.*220C>T		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.3735C>T	p.His1245His	synonymous	Exon 15 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.*220C>T		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.3894C>T	p.His1298His	synonymous	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 18 AN: 111534 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000130

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000475 AC: 5 AN: 105159 AF XY: 0.0000558

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: 0.0000966

Gnomad NFE exome AF: 0.0000997

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 215 AN: 1017518 Hom.: 0 Cov.: 48 AF XY: 0.000271 AC XY: 87 AN XY: 320650

African (AFR) AF: 0.0000414 AC: 1 AN: 24151

American (AMR) AF: 0.0000369 AC: 1 AN: 27132

Ashkenazi Jewish (ASJ) AF: 0.0000559 AC: 1 AN: 17904

East Asian (EAS) AF: 0.00 AC: 0 AN: 26379

South Asian (SAS) AF: 0.00 AC: 0 AN: 47221

European-Finnish (FIN) AF: 0.000142 AC: 5 AN: 35097

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3617

European-Non Finnish (NFE) AF: 0.000252 AC: 200 AN: 793039

Other (OTH) AF: 0.000163 AC: 7 AN: 42978

GnomAD4 genome AF: 0.000161 AC: 18 AN: 111534 Hom.: 0 Cov.: 21 AF XY: 0.000118 AC XY: 4 AN XY: 33796

African (AFR) AF: 0.000130 AC: 4 AN: 30659

American (AMR) AF: 0.00 AC: 0 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6115

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000265 AC: 14 AN: 52891

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.7
DANN	Benign	0.29
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs797045630; hg19: chrX-53264133;