X-71147842-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181303.2(NLGN3):c.93G>C(p.Leu31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.89

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22414586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN3	NM_181303.2 link	c.93G>C	p.Leu31Phe	missense_variant	Exon 2 of 8	ENST00000358741.4	NP_851820.1	Q9NZ94-1X5DNV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4 link	c.93G>C	p.Leu31Phe	missense_variant	Exon 2 of 8	5	NM_181303.2	ENSP00000351591.4		Q9NZ94-1
NLGN3	ENST00000685718.1 link	n.93G>C		non_coding_transcript_exon_variant	Exon 2 of 8			ENSP00000510514.1		A0A8I5QJU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000573

AC:

AN:

174375

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000372

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:

0.00000183

AC:

AN:

1094772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26341

American (AMR)

AF:

0.0000572

AC:

AN:

34960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19313

East Asian (EAS)

AF:

0.00

AC:

AN:

30080

South Asian (SAS)

AF:

0.00

AC:

AN:

53464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840310

Other (OTH)

AF:

0.00

AC:

AN:

45947

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.93G>C (p.L31F) alteration is located in exon 2 (coding exon 1) of the NLGN3 gene. This alteration results from a G to C substitution at nucleotide position 93, causing the leucine (L) at amino acid position 31 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 22, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.20

.;.;.;T

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.96

L;.;L;L

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

0.0010

.;.;B;.

Vest4

0.072

MutPred

0.67

Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);

MVP

0.59

MPC

0.74

ClinPred

0.084

GERP RS

3.9

Varity_R

0.20

gMVP

0.23

Mutation Taster

=85/15

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over