X-53234278-C-T

Variant names:

• chrX-53234278-C-T
• rs191886831
• NM_001111125.3:c.4408G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111125.3(IQSEC2):​c.4408G>A​(p.Ala1470Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,026,508 control chromosomes in the GnomAD database, including 76 homozygotes. There are 3,391 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (10 hom., 120 hem., cov: 14)
  • Exomes 𝑓: 0.012 (66 hom. 3271 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.955
• Publications: 7 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), Ambry Genetics, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029886663).
• BP6: Variant X-53234278-C-T is Benign according to our data. Variant chrX-53234278-C-T is described in ClinVar as Benign. ClinVar VariationId is 129284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00888 (779/87713) while in subpopulation NFE AF = 0.0122 (548/44756). AF 95% confidence interval is 0.0114. There are 10 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 14. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.4408G>A	p.Ala1470Thr	missense	Exon 15 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001410736.1		c.*893G>A		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
	IQSEC2	NM_001441093.1		c.*893G>A		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.4408G>A	p.Ala1470Thr	missense	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.*893G>A		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.4567G>A	p.Ala1523Thr	missense	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 780 AN: 87689 Hom.: 10 Cov.: 14

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.00795

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000374

Gnomad SAS AF: 0.000646

Gnomad FIN AF: 0.00629

Gnomad MID AF: 0.00493

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00536

GnomAD2 exomes AF: 0.00682 AC: 344 AN: 50460 AF XY: 0.00694

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00626

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.0123 AC: 11513 AN: 938795 Hom.: 66 Cov.: 21 AF XY: 0.0121 AC XY: 3271 AN XY: 271161

African (AFR) AF: 0.00146 AC: 31 AN: 21177

American (AMR) AF: 0.00429 AC: 77 AN: 17936

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 200 AN: 14474

East Asian (EAS) AF: 0.0000845 AC: 2 AN: 23675

South Asian (SAS) AF: 0.00138 AC: 47 AN: 33966

European-Finnish (FIN) AF: 0.00847 AC: 284 AN: 33529

Middle Eastern (MID) AF: 0.00631 AC: 23 AN: 3646

European-Non Finnish (NFE) AF: 0.0139 AC: 10453 AN: 750938

Other (OTH) AF: 0.0100 AC: 396 AN: 39454

GnomAD4 genome AF: 0.00888 AC: 779 AN: 87713 Hom.: 10 Cov.: 14 AF XY: 0.00735 AC XY: 120 AN XY: 16325

African (AFR) AF: 0.00193 AC: 45 AN: 23281

American (AMR) AF: 0.00794 AC: 61 AN: 7686

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 31 AN: 2289

East Asian (EAS) AF: 0.000376 AC: 1 AN: 2661

South Asian (SAS) AF: 0.000650 AC: 1 AN: 1538

European-Finnish (FIN) AF: 0.00629 AC: 23 AN: 3658

Middle Eastern (MID) AF: 0.00546 AC: 1 AN: 183

European-Non Finnish (NFE) AF: 0.0122 AC: 548 AN: 44756

Other (OTH) AF: 0.00528 AC: 6 AN: 1136

Alfa AF: 0.0121 Hom.: 190

ExAC AF: 0.00593 AC: 120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Intellectual disability, X-linked 1 (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	18
DANN	Benign	0.97
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.95
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.028
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.67	T
Vest4		0.032
MVP		0.082
MPC		1.0
ClinPred		0.0048	T
GERP RS		2.3
Varity_R		0.090
gMVP		0.089
Mutation Taster		=100/0	polymorphism (auto)

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: rs191886831; hg19: chrX-53263460; COSMIC: COSV64724676; COSMIC: COSV64724676;