rs3747333

chrX-5893491-G-AchrX-5893491-G-CchrX-5893491-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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]

ACMG classification

Verdict is Benign. Variant got -16 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].
• BS2: High Homozygotes in GnomAdExome at 233 XL gene

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: 12980 AN: 107029 Hom.: 1037 Cov.: 20 AF XY: 0.0606 AC XY: 1854 AN XY: 30581 FAILED QC

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0693

Gnomad EAS AF: 0.0940

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0949

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.00756 AC: 1311 AN: 173453 Hom.: 233 AF XY: 0.0138 AC XY: 842 AN XY: 61087

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.00292

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.00623

Gnomad FIN exome AF: 0.000916

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00769

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0571 AC: 58041 AN: 1016946 Hom.: 4236 Cov.: 32 AF XY: 0.0788 AC XY: 27558 AN XY: 349640

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0319

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0641

Gnomad4 FIN exome AF: 0.0802

Gnomad4 NFE exome AF: 0.0505

Gnomad4 OTH exome AF: 0.0727

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.121 AC: 13000 AN: 107064 Hom.: 1039 Cov.: 20 AF XY: 0.0611 AC XY: 1870 AN XY: 30628

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.0649

Gnomad4 ASJ AF: 0.0693

Gnomad4 EAS AF: 0.0949

Gnomad4 SAS AF: 0.0540

Gnomad4 FIN AF: 0.0603

Gnomad4 NFE AF: 0.0949

Gnomad4 OTH AF: 0.120

Alfa AF: 0.118 Hom.: 888

Bravo AF: 0.158

ExAC AF: 0.00102 AC: 118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

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	-	- -
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	-	- -
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. -

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	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;.;T
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;M;M;.;M
MutationTaster	Benign	0.000051	P;P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D;.;D;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.052	T;.;T;.;T
Sift4G	Benign	0.077	T;T;T;.;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.56
MVP		0.95
MPC		2.2
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.37
gMVP		0.86

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

Other links and lift over

dbSNP: rs3747333; hg19: chrX-5811532; COSMIC: COSV52023335;