rs2092376950

Variant names:

• chrX-71147975-G-A
• rs2092376950
• NM_181303.2:c.226G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71147975-G-A
• chrX-71147975-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.226G>A​(p.Ala76Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41
• 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=0.3631891).

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.226G>A	p.Ala76Thr	missense	Exon 2 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.226G>A	p.Ala76Thr	missense	Exon 2 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.226G>A	p.Ala76Thr	missense	Exon 2 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.226G>A	p.Ala76Thr	missense	Exon 2 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.226G>A	p.Ala76Thr	missense	Exon 2 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000395855.7	TSL:1	c.226G>A	p.Ala76Thr	missense	Exon 2 of 5	ENSP00000379196.3	E7EVK0

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1095093 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360641

African (AFR) AF: 0.00 AC: 0 AN: 26340

American (AMR) AF: 0.00 AC: 0 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19308

East Asian (EAS) AF: 0.00 AC: 0 AN: 30131

South Asian (SAS) AF: 0.00 AC: 0 AN: 53937

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839702

Other (OTH) AF: 0.00 AC: 0 AN: 45965

GnomAD4 genome Cov.: 22

Alfa AF: 0.000187 Hom.: 1

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.078
Sift	Benign	0.63	T
Sift4G	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.44		Gain of glycosylation at A76 (P = 0.0056)
MVP		0.70
MPC		0.73
ClinPred		0.38	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.64
Mutation Taster		=67/33	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: rs2092376950; hg19: chrX-70367825;