rs878853147

Variant names:

• chrX-71169399-C-T
• rs878853147
• NM_181303.2:c.1849C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_181303.2(NLGN3):​c.1849C>T​(p.Arg617Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,093,624 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.94
• Publications: 9 publications found

Genes affected

NLGN3 (HGNC:14289): (neuroligin 3) This gene encodes a member of 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. Mutations in this gene may be associated with autism and Asperger syndrome. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Oct 2009]

NLGN3 Gene-Disease associations (from GenCC):

• autism, susceptibility to, X-linked 1

  Inheritance: XL, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: MODERATE Submitted by: Illumina, ClinGen

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant X-71169399-C-T is Pathogenic according to our data. Variant chrX-71169399-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 235850.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181303.2. 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
	NLGN3	NM_181303.2	MANE Select	c.1849C>T	p.Arg617Trp	missense	Exon 8 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.1789C>T	p.Arg597Trp	missense	Exon 7 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.1729C>T	p.Arg577Trp	missense	Exon 6 of 6	NP_001160132.1	X5D7L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN3	ENST00000358741.4	TSL:5 MANE Select	c.1849C>T	p.Arg617Trp	missense	Exon 8 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.1789C>T	p.Arg597Trp	missense	Exon 7 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000476589.2	TSL:1	n.2028C>T		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 359636

African (AFR) AF: 0.00 AC: 0 AN: 26315

American (AMR) AF: 0.00 AC: 0 AN: 34540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30026

South Asian (SAS) AF: 0.00 AC: 0 AN: 53451

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40261

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839644

Other (OTH) AF: 0.00 AC: 0 AN: 45943

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (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	0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.0014	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.84		Loss of methylation at R617 (P = 0.027)
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.98
Mutation Taster		=17/83	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: rs878853147; hg19: chrX-70389249; COSMIC: COSV108891931; COSMIC: COSV108891931;