rs1226379186

Variant names:

• chrX-5893389-G-A
• rs1226379186
• NM_181332.3:c.1879C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_181332.3(NLGN4X):​c.1879C>T​(p.Arg627*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN4X NM_181332.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.31
• Publications: 0 publications found

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

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.233 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.1879C>T	p.Arg627*	stop_gained	Exon 6 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.1879C>T	p.Arg627*	stop_gained	Exon 7 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.1879C>T	p.Arg627*	stop_gained	Exon 6 of 6	NP_001269075.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1879C>T	p.Arg627*	stop_gained	Exon 6 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.1939C>T	p.Arg647*	stop_gained	Exon 6 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.1879C>T	p.Arg627*	stop_gained	Exon 6 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183195 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098036 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363512

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841962

Other (OTH) AF: 0.00 AC: 0 AN: 46083

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 27, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability Uncertain:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		4.3
Vest4		0.81
GERP RS		2.1
Mutation Taster		=35/165	disease causing

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

Other links and lift over

dbSNP: rs1226379186; hg19: chrX-5811430; COSMIC: COSV52023286;