X-5892908-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.23

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]

ACMG classification

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, Uncertain_significance=2, Benign=1}.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN4X	NM_181332.3	c.2360C>T	p.Thr787Met	missense_variant	6/6	ENST00000381095.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN4X	ENST00000381095.8	c.2360C>T	p.Thr787Met	missense_variant	6/6	1	NM_181332.3	P4

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 18 AN: 111005 Hom.: 0 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33211

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: 40 AN: 183527 Hom.: 0 AF XY: 0.000250 AC XY: 17 AN XY: 67953

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.: 0 Cov.: 32 AF XY: 0.000253 AC XY: 92 AN XY: 363591

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: 18 AN: 111062 Hom.: 0 Cov.: 22 AF XY: 0.000210 AC XY: 7 AN XY: 33278

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.: 3

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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

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	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.12	T;T;T;.;T
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.047	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L;.;L
MutationTaster	Benign	0.93	N;N;N;N;N
PrimateAI	Uncertain	0.77	T
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	T
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

Other links and lift over

dbSNP: rs4995611; hg19: chrX-5810949; COSMIC: COSV52025357;