X-71147775-C-T

Variant names:

• chrX-71147775-C-T
• rs777601149
• NM_181303.2:c.26C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_181303.2(NLGN3):​c.26C>T​(p.Ser9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,207,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.325
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048222244).
• BS2: High Hemizygotes in GnomAdExome4 at 3 Unknown,XL gene

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.26C>T	p.Ser9Leu	missense	Exon 2 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.26C>T	p.Ser9Leu	missense	Exon 2 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.26C>T	p.Ser9Leu	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.26C>T	p.Ser9Leu	missense	Exon 2 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.26C>T	p.Ser9Leu	missense	Exon 2 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000395855.7	TSL:1	c.26C>T	p.Ser9Leu	missense	Exon 2 of 5	ENSP00000379196.3	E7EVK0

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 111922 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1095253 Hom.: 0 Cov.: 31 AF XY: 0.00000830 AC XY: 3 AN XY: 361329

African (AFR) AF: 0.0000379 AC: 1 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 34998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30088

South Asian (SAS) AF: 0.00 AC: 0 AN: 53684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4051

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841214

Other (OTH) AF: 0.0000436 AC: 2 AN: 45919

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 111974 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34158

African (AFR) AF: 0.0000648 AC: 2 AN: 30864

American (AMR) AF: 0.000188 AC: 2 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53049

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.33
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.056
Sift	Benign	0.65	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.29		Loss of disorder (P = 0.0146)
MVP		0.64
MPC		0.60
ClinPred		0.061	T
GERP RS		1.3
Varity_R		0.048
gMVP		0.57
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: rs777601149; hg19: chrX-70367625;