dbSNP rs199925687: NLGN3:p.Pro7Gln (chrX-71147769-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_181303.2(NLGN3):c.20C>A(p.Pro7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,310 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.190

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:

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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=0.07382351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN3	NM_181303.2 link	c.20C>A	p.Pro7Gln	missense_variant	Exon 2 of 8	ENST00000358741.4	NP_851820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4 link	c.20C>A	p.Pro7Gln	missense_variant	Exon 2 of 8	5	NM_181303.2	ENSP00000351591.4
NLGN3	ENST00000685718.1 link	n.20C>A		non_coding_transcript_exon_variant	Exon 2 of 8			ENSP00000510514.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26333

American (AMR)

AF:

0.00

AC:

AN:

34941

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19332

East Asian (EAS)

AF:

0.00

AC:

AN:

30067

South Asian (SAS)

AF:

0.00

AC:

AN:

53575

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39351

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3974

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840855

Other (OTH)

AF:

0.00

AC:

AN:

45882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.5

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.098

.;.;.;T

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.85

D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.074

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;.;N;N

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.18

N;N;N;N

REVEL

Benign

0.075

Sift

Benign

0.22

T;T;T;T

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.17

.;.;B;.

Vest4

0.46

MutPred

0.25

Loss of glycosylation at P7 (P = 0.0127);Loss of glycosylation at P7 (P = 0.0127);Loss of glycosylation at P7 (P = 0.0127);Loss of glycosylation at P7 (P = 0.0127);

MVP

0.63

MPC

0.64

ClinPred

0.081

GERP RS

-2.7

Varity_R

0.062

gMVP

0.53

Mutation Taster

=95/5

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

Computational scores

Splicing

Publications

Other links and lift over