rs151073358

Positions:

chrX-5903781-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181332.3(NLGN4X):c.897A>G(p.Ile299Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,210,157 control chromosomes in the GnomAD database, including 16 homozygotes. There are 371 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 8 hom., 171 hem., cov: 23)

Exomes 𝑓: 0.00066 ( 8 hom. 200 hem. )

Consequence

NLGN4X
NM_181332.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0510

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047011375).

BP6

Variant X-5903781-T-C is Benign according to our data. Variant chrX-5903781-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 377303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-5903781-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00687 (769/111906) while in subpopulation AFR AF= 0.0236 (727/30804). AF 95% confidence interval is 0.0222. There are 8 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN4X	NM_181332.3 linkuse as main transcript	c.897A>G	p.Ile299Met	missense_variant	5/6	ENST00000381095.8	NP_851849.1	Q8N0W4-1A0A024RBV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8 linkuse as main transcript	c.897A>G	p.Ile299Met	missense_variant	5/6	1	NM_181332.3	ENSP00000370485.3		Q8N0W4-1

Frequencies

GnomAD3 genomes

AF:

0.00687

AC:

768

AN:

111853

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

171

AN XY:

34033

show subpopulations

Gnomad AFR

AF:

0.0236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00284

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000941

Gnomad OTH

AF:

0.00465

GnomAD3 exomes

AF:

0.00180

AC:

331

AN:

183495

Hom.:

AF XY:

0.000927

AC XY:

AN XY:

67935

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.000838

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:

0.0000366

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000665

AC:

730

AN:

1098251

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

200

AN XY:

363607

show subpopulations

Gnomad4 AFR exome

AF:

0.0226

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000178

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.00687

AC:

769

AN:

111906

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

171

AN XY:

34096

show subpopulations

Gnomad4 AFR

AF:

0.0236

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000941

Gnomad4 OTH

AF:

0.00460

Alfa

AF:

0.00295

Hom.:

Bravo

AF:

0.00744

ESP6500AA

AF:

0.0235

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00178

AC:

216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2017

This alteration is classified as 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

0.048

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.7

DANN

Benign

0.58

DEOGEN2

Benign

0.16

T;T;T;.;T

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.76

.;T;.;T;.

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.51

N;N;N;.;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.12

N;.;N;.;N

REVEL

Benign

0.031

Sift

Benign

0.66

T;.;T;.;T

Sift4G

Benign

0.26

T;T;T;.;T

Polyphen

0.0030

B;B;B;B;B

Vest4

0.17

MVP

0.45

MPC

1.1

ClinPred

0.0045

GERP RS

-2.2

Varity_R

0.19

gMVP

0.52

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