rs144247281

Positions:

• chrX-71155230-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_181303.2(NLGN3):​c.594T>C​(p.Gly198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,210,294 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 342 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00079 (0 hom. 322 hem.)
• Consequence: NLGN3 NM_181303.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.523

Genes affected

NLGN3 (HGNC:14289): (neuroligin 3) This gene encodes a member of 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. Mutations in this gene may be associated with autism and Asperger syndrome. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-71155230-T-C is Benign according to our data. Variant chrX-71155230-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.523 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN3	NM_181303.2	c.594T>C	p.Gly198=	synonymous_variant	5/8	ENST00000358741.4	NP_851820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4	c.594T>C	p.Gly198=	synonymous_variant	5/8	5	NM_181303.2	ENSP00000351591	A1

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 68 AN: 112138 Hom.: 0 Cov.: 24 AF XY: 0.000612 AC XY: 21 AN XY: 34316

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000704 AC: 129 AN: 183298 Hom.: 0 AF XY: 0.000871 AC XY: 59 AN XY: 67760

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00200

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000868

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000790 AC: 868 AN: 1098103 Hom.: 0 Cov.: 31 AF XY: 0.000886 AC XY: 322 AN XY: 363495

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.000206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0000987

Gnomad4 NFE exome AF: 0.000812

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000597 AC: 67 AN: 112191 Hom.: 0 Cov.: 24 AF XY: 0.000582 AC XY: 20 AN XY: 34379

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.000187

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000727 Hom.: 7

Bravo AF: 0.000623

EpiCase AF: 0.00131

EpiControl AF: 0.00125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -

NLGN3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2016

This alteration is classified as likely 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	-0.55
CADD	Benign	5.4
DANN	Benign	0.69

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: rs144247281; hg19: chrX-70375080;