dbSNP rs746346104: NLGN3:p.Arg785Ser (chrX-71169903-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_181303.2(NLGN3):c.2353C>A(p.Arg785Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,632 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. 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. R785H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.58

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40689188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN3	NM_181303.2 link	c.2353C>A	p.Arg785Ser	missense_variant	Exon 8 of 8	ENST00000358741.4	NP_851820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NLGN3	ENST00000358741.4 link	c.2353C>A	p.Arg785Ser	missense_variant	Exon 8 of 8	5	NM_181303.2	ENSP00000351591.4
NLGN3	ENST00000685718.1 link	n.*1700C>A		non_coding_transcript_exon_variant	Exon 8 of 8			ENSP00000510514.1
NLGN3	ENST00000685718.1 link	n.*1700C>A		3_prime_UTR_variant	Exon 8 of 8			ENSP00000510514.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.20e-7

AC:

AN:

1086632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

355212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26049

American (AMR)

AF:

0.00

AC:

AN:

33784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19147

East Asian (EAS)

AF:

0.00

AC:

AN:

29348

South Asian (SAS)

AF:

0.00

AC:

AN:

52603

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836336

Other (OTH)

AF:

0.00

AC:

AN:

45660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

0.24

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.5

.;.;M

PhyloP100

2.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

1.0, 0.99

.;D;D

Vest4

0.41

MutPred

0.51

.;.;Gain of glycosylation at R785 (P = 0.0074);

MVP

0.62

MPC

0.73

ClinPred

0.98

GERP RS

5.2

Varity_R

0.69

gMVP

0.84

Mutation Taster

=41/59

disease causing

(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