X-53227029-C-T

Variant names:

• chrX-53227029-C-T
• rs942926
• ENST00000638869.1:c.*795G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000639796.1(IQSEC2):​c.*817G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (27401 hom., 26083 hem., cov: 22)
  • Exomes 𝑓: 0.75 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 ENST00000639796.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.431
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000639796.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000638869.1	TSL:5	c.*795G>A		3_prime_UTR	Exon 9 of 9	ENSP00000491736.1	A0A1W2PPU7
	IQSEC2	ENST00000639796.1	TSL:3	c.*817G>A		3_prime_UTR	Exon 3 of 3	ENSP00000492252.1	A0A1W2PQS2

Frequencies

GnomAD3 genomes AF: 0.809 AC: 88641 AN: 109552 Hom.: 27414 Cov.: 22

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.958

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.957

Gnomad NFE AF: 0.979

Gnomad OTH AF: 0.827

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 0 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 1 AN: 1

Other (OTH) AF: 0.667 AC: 2 AN: 3

⚠️ 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: InbreedingCoeff AF: 0.809 AC: 88641 AN: 109607 Hom.: 27401 Cov.: 22 AF XY: 0.817 AC XY: 26083 AN XY: 31911

African (AFR) AF: 0.432 AC: 12956 AN: 30000

American (AMR) AF: 0.879 AC: 9053 AN: 10294

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 2503 AN: 2634

East Asian (EAS) AF: 0.735 AC: 2561 AN: 3482

South Asian (SAS) AF: 0.959 AC: 2443 AN: 2547

European-Finnish (FIN) AF: 0.988 AC: 5542 AN: 5610

Middle Eastern (MID) AF: 0.953 AC: 205 AN: 215

European-Non Finnish (NFE) AF: 0.979 AC: 51547 AN: 52664

Other (OTH) AF: 0.827 AC: 1233 AN: 1491

Alfa AF: 0.868 Hom.: 9009

Bravo AF: 0.782

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.55
PhyloP100		0.43

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs942926;

hg19: chrX-53256211;