rs144914894

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_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. 16/21 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:9

Conservation

PhyloP100: 2.24

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

autism, susceptibility to, X-linked 1
Inheritance: Unknown, XL Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: MODERATE Submitted by: Illumina, ClinGen

NLGN3 links:

ENSG00000228427 (HGNC:):

ENSG00000228427 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

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.

BS2

High Hemizygotes in GnomAd4 at 56 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN3	NM_181303.2 link	c.1954A>G	p.Thr652Ala	missense_variant	Exon 8 of 8	ENST00000358741.4	NP_851820.1	Q9NZ94-1X5DNV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLGN3	ENST00000358741.4 link	c.1954A>G	p.Thr652Ala	missense_variant	Exon 8 of 8	5	NM_181303.2	ENSP00000351591.4	Q9NZ94-1
NLGN3	ENST00000685718.1 link	n.*1301A>G		non_coding_transcript_exon_variant	Exon 8 of 8			ENSP00000510514.1	A0A8I5QJU7
NLGN3	ENST00000685718.1 link	n.*1301A>G		3_prime_UTR_variant	Exon 8 of 8			ENSP00000510514.1	A0A8I5QJU7

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

225

AN:

111982

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00226

AC:

413

AN:

182497

AF XY:

0.00222

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 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

African (AFR)

AF:

0.000492

AC:

AN:

26401

American (AMR)

AF:

0.000909

AC:

AN:

35191

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

19382

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30202

South Asian (SAS)

AF:

0.00111

AC:

AN:

54128

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00266

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00483

AC:

4069

AN:

842095

Other (OTH)

AF:

0.00382

AC:

176

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00201

AC:

225

AN:

112036

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

AN XY:

34198

show subpopulations

African (AFR)

AF:

0.000681

AC:

AN:

30846

American (AMR)

AF:

0.000563

AC:

AN:

10663

Ashkenazi Jewish (ASJ)

AF:

0.00227

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00111

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.000490

AC:

AN:

6123

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00347

AC:

184

AN:

53088

Other (OTH)

AF:

0.00131

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00368

Hom.:

163

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 03, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 24, 2016

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. -

Intellectual disability

Benign:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.2

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs144914894

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over