X-5893489-G-C

Variant names:

• chrX-5893489-G-C
• rs3747334
• NM_181332.3:c.1779C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_181332.3(NLGN4X):​c.1779C>G​(p.Leu593Leu) 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:7
• Conservation: PhyloP100: -2.73
• Publications: 11 publications found

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]

NLGN4X Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• autism, susceptibility to, X-linked 2

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 95981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.1779C>G	p.Leu593Leu	synonymous	Exon 6 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.1779C>G	p.Leu593Leu	synonymous	Exon 7 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.1779C>G	p.Leu593Leu	synonymous	Exon 6 of 6	NP_001269075.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1779C>G	p.Leu593Leu	synonymous	Exon 6 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.1839C>G	p.Leu613Leu	synonymous	Exon 6 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.1779C>G	p.Leu593Leu	synonymous	Exon 6 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes AF: 0.121 AC: 12991 AN: 106941 Hom.: 1036 Cov.: 20

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

GnomAD2 exomes AF: 0.00665 AC: 1156 AN: 173708 AF XY: 0.0115

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.164 AC: 3738 AN: 22763

American (AMR) AF: 0.0319 AC: 1099 AN: 34493

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 1124 AN: 18813

East Asian (EAS) AF: 0.103 AC: 3020 AN: 29397

South Asian (SAS) AF: 0.0638 AC: 3360 AN: 52656

European-Finnish (FIN) AF: 0.0799 AC: 3089 AN: 38640

Middle Eastern (MID) AF: 0.0852 AC: 327 AN: 3836

European-Non Finnish (NFE) AF: 0.0496 AC: 38521 AN: 776304

Other (OTH) AF: 0.0723 AC: 3118 AN: 43155

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.216 AC: 6118 AN: 28347

American (AMR) AF: 0.0649 AC: 663 AN: 10217

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 184 AN: 2608

East Asian (EAS) AF: 0.0936 AC: 318 AN: 3397

South Asian (SAS) AF: 0.0541 AC: 135 AN: 2497

European-Finnish (FIN) AF: 0.0606 AC: 349 AN: 5763

Middle Eastern (MID) AF: 0.105 AC: 22 AN: 209

European-Non Finnish (NFE) AF: 0.0950 AC: 4924 AN: 51823

Other (OTH) AF: 0.120 AC: 176 AN: 1465

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0402 Hom.: 291

Bravo AF: 0.158

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Oct 16, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Dec 13, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.030
DANN	Benign	0.53
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3747334; hg19: chrX-5811530;