X-5892908-G-A

Position:

chrX-5892908-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN4X	NM_181332.3 linkuse as main transcript	c.2360C>T	p.Thr787Met	missense_variant	6/6	ENST00000381095.8	NP_851849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8 linkuse as main transcript	c.2360C>T	p.Thr787Met	missense_variant	6/6	1	NM_181332.3	ENSP00000370485	P4	Q8N0W4-1

Frequencies

GnomAD3 genomes

AF:

0.000162

AC:

AN:

111005

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

33211

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

GnomAD3 exomes

AF:

0.000218

AC:

AN:

183527

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

67953

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 SAS 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

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000304

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000162

AC:

AN:

111062

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

AN XY:

33278

show subpopulations

Gnomad4 AFR

AF:

0.0000328

Gnomad4 AMR

AF:

0.000192

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000283

Gnomad4 OTH

AF:

0.00

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	NLGN4X: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2014

- -

Autism, susceptibility to, X-linked 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 08, 2019

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2017

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

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

MutationTaster

Benign

0.93

N;N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over