X-5892973-G-C

Variant names:

• chrX-5892973-G-C
• rs770890880
• NM_181332.3:c.2295C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_181332.3(NLGN4X):​c.2295C>G​(p.Arg765Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,209,453 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.000040 (0 hom. 13 hem.)
• Consequence: NLGN4X NM_181332.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.128
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-5892973-G-C is Benign according to our data. Variant chrX-5892973-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3036042.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.128 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.2295C>G	p.Arg765Arg	synonymous_variant	Exon 6 of 6	ENST00000381095.8	NP_851849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8	c.2295C>G	p.Arg765Arg	synonymous_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 35 AN: 111185 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000872 AC: 16 AN: 183528 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000401 AC: 44 AN: 1098268 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 13 AN XY: 363622

African (AFR) AF: 0.00159 AC: 42 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842149

Other (OTH) AF: 0.0000434 AC: 2 AN: 46098

GnomAD4 genome AF: 0.000315 AC: 35 AN: 111185 Hom.: 0 Cov.: 22 AF XY: 0.000180 AC XY: 6 AN XY: 33363

African (AFR) AF: 0.00115 AC: 35 AN: 30529

American (AMR) AF: 0.00 AC: 0 AN: 10443

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53027

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NLGN4X-related disorder Benign:1

May 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.7
DANN	Benign	0.42
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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: rs770890880; hg19: chrX-5811014;