X-5893489-G-A

Variant names:

• chrX-5893489-G-A
• rs3747334
• NM_181332.3:c.1779C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_181332.3(NLGN4X):​c.1779C>T​(p.Leu593Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,162,125 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L593L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.0000066 (0 hom. 3 hem.)
• Consequence: NLGN4X NM_181332.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.73
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.1779C>T	p.Leu593Leu	synonymous	Exon 6 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.1779C>T	p.Leu593Leu	synonymous	Exon 7 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.1779C>T	p.Leu593Leu	synonymous	Exon 6 of 6	NP_001269075.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1779C>T	p.Leu593Leu	synonymous	Exon 6 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.1839C>T	p.Leu613Leu	synonymous	Exon 6 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.1779C>T	p.Leu593Leu	synonymous	Exon 6 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes AF: 0.00000927 AC: 1 AN: 107853 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000292

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

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173708 AF XY: 0.0000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000758

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000664 AC: 7 AN: 1054272 Hom.: 0 Cov.: 32 AF XY: 0.00000854 AC XY: 3 AN XY: 351362

African (AFR) AF: 0.00 AC: 0 AN: 24161

American (AMR) AF: 0.00 AC: 0 AN: 34952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19074

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29864

South Asian (SAS) AF: 0.00 AC: 0 AN: 53434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40318

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4015

European-Non Finnish (NFE) AF: 0.00000498 AC: 4 AN: 803914

Other (OTH) AF: 0.0000225 AC: 1 AN: 44540

GnomAD4 genome AF: 0.00000927 AC: 1 AN: 107853 Hom.: 0 Cov.: 20 AF XY: 0.0000326 AC XY: 1 AN XY: 30631

African (AFR) AF: 0.00 AC: 0 AN: 28712

American (AMR) AF: 0.00 AC: 0 AN: 10254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.000292 AC: 1 AN: 3428

South Asian (SAS) AF: 0.00 AC: 0 AN: 2515

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52196

Other (OTH) AF: 0.00 AC: 0 AN: 1449

Alfa AF: 0.00 Hom.: 291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.032
DANN	Benign	0.58
PhyloP100		-2.7
Mutation Taster		=100/0	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: rs3747334; hg19: chrX-5811530;