rs748757954

Variant names:

• chrX-71169793-G-A
• rs748757954
• NM_181303.2:c.2243G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71169793-G-A
• chrX-71169793-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27148575).

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.2243G>A	p.Arg748Gln	missense	Exon 8 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.2183G>A	p.Arg728Gln	missense	Exon 7 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.2123G>A	p.Arg708Gln	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.2243G>A	p.Arg748Gln	missense	Exon 8 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.2183G>A	p.Arg728Gln	missense	Exon 7 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000476589.2	TSL:1	n.2422G>A		non_coding_transcript_exon	Exon 7 of 7

Frequencies

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

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 173379 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: 0.00

Gnomad OTH exome 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

African (AFR) AF: 0.0000379 AC: 1 AN: 26365

American (AMR) AF: 0.00 AC: 0 AN: 34959

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19274

East Asian (EAS) AF: 0.00 AC: 0 AN: 30129

South Asian (SAS) AF: 0.00 AC: 0 AN: 53746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40139

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840682

Other (OTH) AF: 0.00 AC: 0 AN: 45939

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

African (AFR) AF: 0.00 AC: 0 AN: 30819

American (AMR) AF: 0.00 AC: 0 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6121

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53065

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.030	D
Polyphen		0.84	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
Mutation Taster		=77/23	polymorphism

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