rs778014568

Variant names:

• chrX-5893381-G-A
• rs778014568
• NM_181332.3:c.1887C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_181332.3(NLGN4X):​c.1887C>T​(p.Pro629Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,208,100 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.000021 (0 hom. 6 hem.)
• Consequence: NLGN4X NM_181332.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.17
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant X-5893381-G-A is Benign according to our data. Variant chrX-5893381-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211680.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 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.1887C>T	p.Pro629Pro	synonymous	Exon 6 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.1887C>T	p.Pro629Pro	synonymous	Exon 7 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.1887C>T	p.Pro629Pro	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.1887C>T	p.Pro629Pro	synonymous	Exon 6 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.1947C>T	p.Pro649Pro	synonymous	Exon 6 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.1887C>T	p.Pro629Pro	synonymous	Exon 6 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes AF: 0.0000727 AC: 8 AN: 109988 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000134

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: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.000674

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183236 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

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: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000209 AC: 23 AN: 1098060 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 6 AN XY: 363536

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4132

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 841985

Other (OTH) AF: 0.0000217 AC: 1 AN: 46085

GnomAD4 genome AF: 0.0000818 AC: 9 AN: 110040 Hom.: 0 Cov.: 21 AF XY: 0.0000929 AC XY: 3 AN XY: 32290

African (AFR) AF: 0.000167 AC: 5 AN: 29940

American (AMR) AF: 0.00 AC: 0 AN: 10412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3484

South Asian (SAS) AF: 0.00 AC: 0 AN: 2494

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5919

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52776

Other (OTH) AF: 0.000666 AC: 1 AN: 1502

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000831

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.052
DANN	Benign	0.39
PhyloP100		-1.2
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: rs778014568; hg19: chrX-5811422; COSMIC: COSV52013578;