rs3747333

Variant names:

• chrX-5893491-G-A
• rs3747333
• NM_181332.3:c.1777C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-5893491-G-A
• chrX-5893491-G-C
• chrX-5893491-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_181332.3(NLGN4X):​c.1777C>T​(p.Leu593Phe) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L593L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1039 hom., 1870 hem., cov: 20)
  • Exomes 𝑓: 0.057 (4236 hom. 27558 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.68
• Publications: 18 publications found

Genes affected

NLGN4X (HGNC:14287): (neuroligin 4 X-linked) This gene encodes a member of the type-B carboxylesterase/lipase protein family. The encoded protein belongs to 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. The encoded protein interacts with discs large homolog 4 (DLG4). Mutations in this gene have been associated with autism and Asperger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

NLGN4X Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• autism, susceptibility to, X-linked 2

  Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014665186).
• BP6: Variant X-5893491-G-A is Benign according to our data. Variant chrX-5893491-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181332.3. 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
	NLGN4X	NM_181332.3	MANE Select	c.1777C>T	p.Leu593Phe	missense	Exon 6 of 6	NP_851849.1	Q8N0W4-1
	NLGN4X	NM_001282145.2		c.1777C>T	p.Leu593Phe	missense	Exon 7 of 7	NP_001269074.1	Q8N0W4-1
	NLGN4X	NM_001282146.2		c.1777C>T	p.Leu593Phe	missense	Exon 6 of 6	NP_001269075.1	Q8N0W4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1777C>T	p.Leu593Phe	missense	Exon 6 of 6	ENSP00000370485.3	Q8N0W4-1
	NLGN4X	ENST00000538097.6	TSL:1	c.1837C>T	p.Leu613Phe	missense	Exon 6 of 6	ENSP00000439203.3	Q8N0W4-2
	NLGN4X	ENST00000275857.10	TSL:1	c.1777C>T	p.Leu593Phe	missense	Exon 6 of 6	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 12980 AN: 107029 Hom.: 1037 Cov.: 20

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0693

Gnomad EAS AF: 0.0940

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0949

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.00756 AC: 1311 AN: 173453 AF XY: 0.0138

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.00292

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.000916

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00769

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0571 AC: 58041 AN: 1016946 Hom.: 4236 Cov.: 32 AF XY: 0.0788 AC XY: 27558 AN XY: 349640

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.168 AC: 3832 AN: 22764

American (AMR) AF: 0.0319 AC: 1102 AN: 34503

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 1132 AN: 18799

East Asian (EAS) AF: 0.103 AC: 3019 AN: 29360

South Asian (SAS) AF: 0.0641 AC: 3371 AN: 52603

European-Finnish (FIN) AF: 0.0802 AC: 3101 AN: 38654

Middle Eastern (MID) AF: 0.0861 AC: 330 AN: 3832

European-Non Finnish (NFE) AF: 0.0505 AC: 39025 AN: 773394

Other (OTH) AF: 0.0727 AC: 3129 AN: 43037

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.121 AC: 13000 AN: 107064 Hom.: 1039 Cov.: 20 AF XY: 0.0611 AC XY: 1870 AN XY: 30628

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.215 AC: 6112 AN: 28388

American (AMR) AF: 0.0649 AC: 665 AN: 10242

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 180 AN: 2599

East Asian (EAS) AF: 0.0949 AC: 323 AN: 3405

South Asian (SAS) AF: 0.0540 AC: 135 AN: 2502

European-Finnish (FIN) AF: 0.0603 AC: 348 AN: 5768

Middle Eastern (MID) AF: 0.105 AC: 22 AN: 209

European-Non Finnish (NFE) AF: 0.0949 AC: 4917 AN: 51833

Other (OTH) AF: 0.120 AC: 175 AN: 1464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.203 Hom.: 1923

Bravo AF: 0.158

ExAC AF: 0.00102 AC: 118

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autism, susceptibility to, X-linked 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.38
Sift	Benign	0.052	T
Sift4G	Benign	0.077	T
Polyphen		0.99	D
Vest4		0.56
MVP		0.95
MPC		2.2
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.37
gMVP		0.86
Mutation Taster		=100/0	polymorphism (auto)

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: rs3747333; hg19: chrX-5811532; COSMIC: COSV52023335;