X-71147769-C-A

Variant names:

• chrX-71147769-C-A
• rs199925687
• NM_181303.2:c.20C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181303.2(NLGN3):​c.20C>A​(p.Pro7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,310 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07382351).

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.20C>A	p.Pro7Gln	missense	Exon 2 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.20C>A	p.Pro7Gln	missense	Exon 2 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.20C>A	p.Pro7Gln	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.20C>A	p.Pro7Gln	missense	Exon 2 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.20C>A	p.Pro7Gln	missense	Exon 2 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000395855.7	TSL:1	c.20C>A	p.Pro7Gln	missense	Exon 2 of 5	ENSP00000379196.3	E7EVK0

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094310 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360538

African (AFR) AF: 0.00 AC: 0 AN: 26333

American (AMR) AF: 0.00 AC: 0 AN: 34941

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30067

South Asian (SAS) AF: 0.00 AC: 0 AN: 53575

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39351

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3974

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840855

Other (OTH) AF: 0.00 AC: 0 AN: 45882

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.5
DANN	Benign	0.83
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.075
Sift	Benign	0.22	T
Sift4G	Benign	0.30	T
Polyphen		0.17	B
Vest4		0.46
MutPred		0.25		Loss of glycosylation at P7 (P = 0.0127)
MVP		0.63
MPC		0.64
ClinPred		0.081	T
GERP RS		-2.7
Varity_R		0.062
gMVP		0.53
Mutation Taster		=95/5	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: rs199925687; hg19: chrX-70367619;