rs746346104

Variant names:

• chrX-71169903-C-T
• rs746346104
• NM_181303.2:c.2353C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-71169903-C-T
• chrX-71169903-C-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_181303.2(NLGN3):​c.2353C>T​(p.Arg785Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,197,425 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. 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. R785H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 3 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.58
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37803826).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL,Unknown 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.2353C>T	p.Arg785Cys	missense	Exon 8 of 8	NP_851820.1	X5DNV3
	NLGN3	NM_018977.4		c.2293C>T	p.Arg765Cys	missense	Exon 7 of 7	NP_061850.2	Q9NZ94-2
	NLGN3	NM_001166660.2		c.2233C>T	p.Arg745Cys	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.2353C>T	p.Arg785Cys	missense	Exon 8 of 8	ENSP00000351591.4	Q9NZ94-1
	NLGN3	ENST00000374051.7	TSL:1	c.2293C>T	p.Arg765Cys	missense	Exon 7 of 7	ENSP00000363163.3	Q9NZ94-2
	NLGN3	ENST00000476589.2	TSL:1	n.2532C>T		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0000542 AC: 6 AN: 110742 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000329

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: 0.0127

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156778 AF XY: 0.00

Gnomad AFR exome AF: 0.0000901

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: 0.0000138 AC: 15 AN: 1086630 Hom.: 0 Cov.: 32 AF XY: 0.00000845 AC XY: 3 AN XY: 355208

African (AFR) AF: 0.00 AC: 0 AN: 26049

American (AMR) AF: 0.00 AC: 0 AN: 33786

Ashkenazi Jewish (ASJ) AF: 0.0000522 AC: 1 AN: 19147

East Asian (EAS) AF: 0.00 AC: 0 AN: 29348

South Asian (SAS) AF: 0.0000760 AC: 4 AN: 52602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39581

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.0000108 AC: 9 AN: 836332

Other (OTH) AF: 0.0000219 AC: 1 AN: 45660

GnomAD4 genome AF: 0.0000451 AC: 5 AN: 110795 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33059

African (AFR) AF: 0.0000328 AC: 1 AN: 30481

American (AMR) AF: 0.00 AC: 0 AN: 10493

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2577

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5949

Middle Eastern (MID) AF: 0.00930 AC: 2 AN: 215

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52755

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.32
MVP		0.74
MPC		1.0
ClinPred		0.72	D
GERP RS		5.2
Varity_R		0.69
gMVP		0.80
Mutation Taster		=60/40	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: rs746346104; hg19: chrX-70389753; COSMIC: COSV62442741; COSMIC: COSV62442741;