chrX-5893489-G-C

Position:

• chrX-5893489-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_181332.3(NLGN4X):​c.1779C>G​(p.Leu593=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1038 hom., 1867 hem., cov: 20)
  • Exomes 𝑓: 0.056 (4048 hom. 27421 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN4X NM_181332.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.73

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-5893489-G-C is Benign according to our data. Variant chrX-5893489-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 95981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-5893489-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN4X	NM_181332.3	c.1779C>G	p.Leu593=	synonymous_variant	6/6	ENST00000381095.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN4X	ENST00000381095.8	c.1779C>G	p.Leu593=	synonymous_variant	6/6	1	NM_181332.3	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12991 AN: 106941 Hom.: 1036 Cov.: 20 AF XY: 0.0607 AC XY: 1850 AN XY: 30485 FAILED QC

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.0928

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.00665 AC: 1156 AN: 173708 Hom.: 226 AF XY: 0.0115 AC XY: 701 AN XY: 60956

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00349

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0107

Gnomad SAS exome AF: 0.00567

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00673

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0563 AC: 57396 AN: 1020057 Hom.: 4048 Cov.: 32 AF XY: 0.0785 AC XY: 27421 AN XY: 349499

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0319

Gnomad4 ASJ exome AF: 0.0597

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0638

Gnomad4 FIN exome AF: 0.0799

Gnomad4 NFE exome AF: 0.0496

Gnomad4 OTH exome AF: 0.0723

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.122 AC: 13012 AN: 106979 Hom.: 1038 Cov.: 20 AF XY: 0.0611 AC XY: 1867 AN XY: 30535

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.0649

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.0936

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0606

Gnomad4 NFE AF: 0.0950

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0402 Hom.: 291

Bravo AF: 0.158

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -

not specified Benign:2

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	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.030
DANN	Benign	0.53

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: rs3747334; hg19: chrX-5811530;