rs144914894

Positions:

chrX-71169504-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_181303.2(NLGN3):c.1954A>G(p.Thr652Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,210,181 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,432 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., 56 hem., cov: 22)

Exomes 𝑓: 0.0040 ( 10 hom. 1376 hem. )

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.24

Variant links:

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]

NLGN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLGN3. . Gene score misZ 4.206 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked complex neurodevelopmental disorder, autism, susceptibility to, X-linked 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.005596161).

BP6

Variant X-71169504-A-G is Benign according to our data. Variant chrX-71169504-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 167363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71169504-A-G is described in Lovd as [Likely_benign]. Variant chrX-71169504-A-G is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 56 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2 linkuse as main transcript	c.1954A>G	p.Thr652Ala	missense_variant	8/8	ENST00000358741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4 linkuse as main transcript	c.1954A>G	p.Thr652Ala	missense_variant	8/8	5	NM_181303.2	A1	Q9NZ94-1

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

225

AN:

111982

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

AN XY:

34134

show subpopulations

Gnomad AFR

AF:

0.000682

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000563

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00111

Gnomad FIN

AF:

0.000490

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00226

AC:

413

AN:

182497

Hom.:

AF XY:

0.00222

AC XY:

149

AN XY:

67089

show subpopulations

Gnomad AFR exome

AF:

0.000306

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000947

Gnomad FIN exome

AF:

0.000314

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00401

AC:

4408

AN:

1098145

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

1376

AN XY:

363503

show subpopulations

Gnomad4 AFR exome

AF:

0.000492

Gnomad4 AMR exome

AF:

0.000909

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.000568

Gnomad4 NFE exome

AF:

0.00483

Gnomad4 OTH exome

AF:

0.00382

GnomAD4 genome

AF:

0.00201

AC:

225

AN:

112036

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

AN XY:

34198

show subpopulations

Gnomad4 AFR

AF:

0.000681

Gnomad4 AMR

AF:

0.000563

Gnomad4 ASJ

AF:

0.00227

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00111

Gnomad4 FIN

AF:

0.000490

Gnomad4 NFE

AF:

0.00347

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00388

Hom.:

162

Bravo

AF:

0.00243

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00401

AC:

ExAC

AF:

0.00227

AC:

276

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2017	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2016

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

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.11

.;.;T

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.67

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.51

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.064

MVP

0.69

MPC

0.26

ClinPred

0.0056

GERP RS

4.8

Varity_R

0.20

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over