rs999173635

Variant names:

• chrX-5892852-T-C
• rs999173635
• NM_181332.3:c.2416A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-5892852-T-C
• chrX-5892852-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181332.3(NLGN4X):​c.2416A>G​(p.Asn806Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000728 in 1,098,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000073 (0 hom. 1 hem.)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.10
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19722909).

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.2416A>G	p.Asn806Asp	missense	Exon 6 of 6	NP_851849.1	Q8N0W4-1
	NLGN4X	NM_001282145.2		c.2416A>G	p.Asn806Asp	missense	Exon 7 of 7	NP_001269074.1	Q8N0W4-1
	NLGN4X	NM_001282146.2		c.2416A>G	p.Asn806Asp	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.2416A>G	p.Asn806Asp	missense	Exon 6 of 6	ENSP00000370485.3	Q8N0W4-1
	NLGN4X	ENST00000538097.6	TSL:1	c.2476A>G	p.Asn826Asp	missense	Exon 6 of 6	ENSP00000439203.3	Q8N0W4-2
	NLGN4X	ENST00000275857.10	TSL:1	c.2416A>G	p.Asn806Asp	missense	Exon 6 of 6	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183483 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098183 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363537

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

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842072

Other (OTH) AF: 0.00 AC: 0 AN: 46098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000545952), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	NLGN4X-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.13
Sift	Benign	0.053	T
Sift4G	Benign	0.61	T
Polyphen		0.13	B
Vest4		0.35
MVP		0.79
MPC		1.3
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.29
Mutation Taster		=89/11	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: rs999173635; hg19: chrX-5810893;