rs1555913640

Variant names:

• chrX-5893521-G-A
• rs1555913640
• NM_181332.3:c.1747C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_181332.3(NLGN4X):​c.1747C>T​(p.Arg583Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.49
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant X-5893521-G-A is Pathogenic according to our data. Variant chrX-5893521-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 521221.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.1747C>T	p.Arg583Trp	missense	Exon 6 of 6	NP_851849.1	Q8N0W4-1
	NLGN4X	NM_001282145.2		c.1747C>T	p.Arg583Trp	missense	Exon 7 of 7	NP_001269074.1	Q8N0W4-1
	NLGN4X	NM_001282146.2		c.1747C>T	p.Arg583Trp	missense	Exon 6 of 6	NP_001269075.1	Q8N0W4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1747C>T	p.Arg583Trp	missense	Exon 6 of 6	ENSP00000370485.3	Q8N0W4-1
	NLGN4X	ENST00000538097.6	TSL:1	c.1807C>T	p.Arg603Trp	missense	Exon 6 of 6	ENSP00000439203.3	Q8N0W4-2
	NLGN4X	ENST00000275857.10	TSL:1	c.1747C>T	p.Arg583Trp	missense	Exon 6 of 6	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1096841 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362341

African (AFR) AF: 0.00 AC: 0 AN: 26338

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840897

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.90
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1555913640; hg19: chrX-5811562; COSMIC: COSV104997530;