rs748757954

chrX-71169793-G-AchrX-71169793-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_181303.2(NLGN3):c.2243G>A(p.Arg748Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,095,333 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R748L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.77

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NLGN3
• BP4: Computational evidence support a benign effect (MetaRNN=0.27148575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2	c.2243G>A	p.Arg748Gln	missense_variant	8/8	ENST00000358741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4	c.2243G>A	p.Arg748Gln	missense_variant	8/8	5	NM_181303.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111990 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34152

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095333 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361005

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000893 AC: 1 AN: 111990 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34152

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 02, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	26
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.84, 0.76	.;P;P
Vest4		0.32
MutPred		0.23		.;.;Gain of glycosylation at P744 (P = 0.1132);
MVP		0.87
MPC		0.57
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.52

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: rs748757954; hg19: chrX-70389643; COSMIC: COSV62442318; COSMIC: COSV62442318;