X-5892908-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_181332.3(NLGN4X):c.2360C>T(p.Thr787Met) variant causes a missense change. The variant allele was found at a frequency of 0.000241 in 1,209,295 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T787T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00025 ( 0 hom. 92 hem. )

Consequence

NLGN4X
NM_181332.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.23

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047440022).

BP6

Variant X-5892908-G-A is Benign according to our data. Variant chrX-5892908-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211681.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3 link	c.2360C>T	p.Thr787Met	missense_variant	Exon 6 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.2360C>T	p.Thr787Met	missense_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3		Q8N0W4-1

Frequencies

GnomAD3 genomes

AF:

0.000162

AC:

AN:

111005

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

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:

0.000283

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000218

AC:

AN:

183527

AF XY:

0.000250

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000390

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000249

AC:

274

AN:

1098233

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

AN XY:

363591

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

26403

American (AMR)

AF:

0.000142

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:

54146

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000304

AC:

256

AN:

842117

Other (OTH)

AF:

0.000174

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000162

AC:

AN:

111062

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

AN XY:

33278

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30524

American (AMR)

AF:

0.000192

AC:

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3492

South Asian (SAS)

AF:

0.00

AC:

AN:

2586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000283

AC:

AN:

53020

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLGN4X: BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Oct 20, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autism, susceptibility to, X-linked 2

Uncertain:1

Jul 08, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 28, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.12

T;T;T;.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.68

.;T;.;T;.

M_CAP

Benign

0.0072

MetaRNN

Benign

0.047

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L;L;.;L

PhyloP100

4.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.56

N;.;N;.;N

REVEL

Benign

0.025

Sift

Benign

0.14

T;.;T;.;T

Sift4G

Benign

0.10

T;T;T;.;T

Polyphen

0.0020

B;B;B;B;B

Vest4

0.18

MVP

0.27

MPC

1.1

ClinPred

0.026

GERP RS

3.8

Varity_R

0.062

gMVP

0.45

Mutation Taster

=100/0

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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X-5892908-G-A

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