dbSNP rs199769855: NLGN4X:p.Arg319Trp (chrX-5903723-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_181332.3(NLGN4X):c.955C>T(p.Arg319Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,893 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R319R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

NLGN4X
NM_181332.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.61

Publications

4 publications found

Variant links:

Genes affected

NLGN4X (HGNC:14287): (neuroligin 4 X-linked) This gene encodes a member of the type-B carboxylesterase/lipase protein family. The encoded protein belongs to 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. The encoded protein interacts with discs large homolog 4 (DLG4). Mutations in this gene have been associated with autism and Asperger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

NLGN4X Gene-Disease associations (from GenCC):

X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
autism, susceptibility to, X-linked 2
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

NLGN4X links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3 link	c.955C>T	p.Arg319Trp	missense_variant	Exon 5 of 6	ENST00000381095.8	NP_851849.1	Q8N0W4-1A0A024RBV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8 link	c.955C>T	p.Arg319Trp	missense_variant	Exon 5 of 6	1	NM_181332.3	ENSP00000370485.3		Q8N0W4-1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098261

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363619

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842145

Other (OTH)

AF:

0.00

AC:

AN:

46098

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30662

American (AMR)

AF:

0.00

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6071

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53104

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D;D;.;D

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

.;D;.;D;.

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

4.3

H;H;H;.;H

PhyloP100

4.6

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.3

D;.;D;.;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.55

MutPred

0.89

Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);.;Loss of solvent accessibility (P = 0.086);

MVP

0.87

MPC

2.1

ClinPred

1.0

GERP RS

3.0

Varity_R

0.92

gMVP

0.93

Mutation Taster

=52/48

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