chrX-53234268-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001111125.3(IQSEC2):​c.4418C>T​(p.Pro1473Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 975,899 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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). Synonymous variant affecting the same amino acid position (i.e. P1473P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 15)
Exomes 𝑓: 0.0000041 ( 0 hom. 2 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

1
3
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.93
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.19100425).
BP6
Variant X-53234268-G-A is Benign according to our data. Variant chrX-53234268-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1218277.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IQSEC2NM_001111125.3 linkuse as main transcriptc.4418C>T p.Pro1473Leu missense_variant 15/15 ENST00000642864.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IQSEC2ENST00000642864.1 linkuse as main transcriptc.4418C>T p.Pro1473Leu missense_variant 15/15 NM_001111125.3 P1Q5JU85-2

Frequencies

GnomAD3 genomes
Cov.:
15
GnomAD3 exomes
AF:
0.0000166
AC:
1
AN:
60405
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
10167
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000480
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
4
AN:
975899
Hom.:
0
Cov.:
21
AF XY:
0.00000678
AC XY:
2
AN XY:
294809
show subpopulations
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:
0.00000516
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
15

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024IQSEC2: PM2, PP2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 24, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Intellectual disability, X-linked 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 30, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Uncertain
24
DANN
Uncertain
0.99
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
.;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.84
D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.4
N;.
REVEL
Benign
0.10
Sift
Uncertain
0.0010
D;.
Sift4G
Benign
0.16
T;.
Vest4
0.16
MutPred
0.27
Loss of glycosylation at P1473 (P = 0.025);Loss of glycosylation at P1473 (P = 0.025);
MVP
0.22
MPC
1.1
ClinPred
0.33
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.13

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: rs1556858927; hg19: chrX-53263450; API