chrX-53234223-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_ModerateBP4

The NM_001111125.3(IQSEC2):ā€‹c.4463T>Cā€‹(p.Val1488Ala) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 17)
Exomes š‘“: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

5
2
8

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.11
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5
Variant X-53234223-A-G is Pathogenic according to our data. Variant chrX-53234223-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449855.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.3111923). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IQSEC2NM_001111125.3 linkuse as main transcriptc.4463T>C p.Val1488Ala missense_variant 15/15 ENST00000642864.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IQSEC2ENST00000642864.1 linkuse as main transcriptc.4463T>C p.Val1488Ala missense_variant 15/15 NM_001111125.3 P1Q5JU85-2

Frequencies

GnomAD3 genomes
Cov.:
17
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
923177
Hom.:
0
Cov.:
17
AF XY:
0.00
AC XY:
0
AN XY:
262443
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
17

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxAug 23, 2019Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
23
DANN
Uncertain
0.99
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.61
.;T
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.5
N;.
REVEL
Benign
0.18
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Vest4
0.43
MutPred
0.10
Gain of glycosylation at S1485 (P = 0.1738);Gain of glycosylation at S1485 (P = 0.1738);
MVP
0.41
MPC
1.3
ClinPred
0.93
D
GERP RS
3.1
Varity_R
0.36
gMVP
0.21

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1556858900; hg19: chrX-53263405; API