rs121917893

Positions:

• chrX-71167508-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_181303.2(NLGN3):​c.1411C>T​(p.Arg471Cys) variant causes a missense 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 risk factor (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLGN3. . Gene score misZ 4.206 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked complex neurodevelopmental disorder, autism, susceptibility to, X-linked 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN3	NM_181303.2	c.1411C>T	p.Arg471Cys	missense_variant	7/8	ENST00000358741.4	NP_851820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4	c.1411C>T	p.Arg471Cys	missense_variant	7/8	5	NM_181303.2	ENSP00000351591	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism, susceptibility to, X-linked 1 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;.;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.1	D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.73
MutPred		0.84		.;.;.;Loss of disorder (P = 0.0153);
MVP		0.97
MPC		3.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.99

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: rs121917893; hg19: chrX-70387358; COSMIC: COSV100705101;