rs3747333
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_181332.3(NLGN4X):c.1777C>T(p.Leu593Phe) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L593L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.12 ( 1039 hom., 1870 hem., cov: 20)
Exomes 𝑓: 0.057 ( 4236 hom. 27558 hem. )
Failed GnomAD Quality Control
Consequence
NLGN4X
NM_181332.3 missense
NM_181332.3 missense
Scores
1
8
6
Clinical Significance
Conservation
PhyloP100: 4.68
Genes affected
NLGN4X (HGNC:14287): (neuroligin 4 X-linked) This gene encodes a member of the type-B carboxylesterase/lipase protein family. The encoded protein belongs to a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses. The encoded protein interacts with discs large homolog 4 (DLG4). Mutations in this gene have been associated with autism and Asperger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.014665186).
BP6
?
Variant X-5893491-G-A is Benign according to our data. Variant chrX-5893491-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-5893491-G-A is described in Lovd as [Benign]. Variant chrX-5893491-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLGN4X | NM_181332.3 | c.1777C>T | p.Leu593Phe | missense_variant | 6/6 | ENST00000381095.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLGN4X | ENST00000381095.8 | c.1777C>T | p.Leu593Phe | missense_variant | 6/6 | 1 | NM_181332.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 12980AN: 107029Hom.: 1037 Cov.: 20 AF XY: 0.0606 AC XY: 1854AN XY: 30581 FAILED QC
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GnomAD3 exomes AF: 0.00756 AC: 1311AN: 173453Hom.: 233 AF XY: 0.0138 AC XY: 842AN XY: 61087
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0571 AC: 58041AN: 1016946Hom.: 4236 Cov.: 32 AF XY: 0.0788 AC XY: 27558AN XY: 349640
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.121 AC: 13000AN: 107064Hom.: 1039 Cov.: 20 AF XY: 0.0611 AC XY: 1870AN XY: 30628
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 16, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Autism, susceptibility to, X-linked 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T;.;T
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.;M
MutationTaster
Benign
P;P;P;P;P
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;.;D
REVEL
Uncertain
Sift
Benign
T;.;T;.;T
Sift4G
Benign
T;T;T;.;T
Polyphen
D;D;D;D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at