rs1412018300

Variant names:

• chrX-5903624-C-T
• rs1412018300
• NM_181332.3:c.1054G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181332.3(NLGN4X):​c.1054G>A​(p.Asp352Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,268 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1054G>A	p.Asp352Asn	missense	Exon 5 of 6	NP_851849.1	Q8N0W4-1
	NLGN4X	NM_001282145.2		c.1054G>A	p.Asp352Asn	missense	Exon 6 of 7	NP_001269074.1	Q8N0W4-1
	NLGN4X	NM_001282146.2		c.1054G>A	p.Asp352Asn	missense	Exon 5 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.1054G>A	p.Asp352Asn	missense	Exon 5 of 6	ENSP00000370485.3	Q8N0W4-1
	NLGN4X	ENST00000538097.6	TSL:1	c.1114G>A	p.Asp372Asn	missense	Exon 5 of 6	ENSP00000439203.3	Q8N0W4-2
	NLGN4X	ENST00000275857.10	TSL:1	c.1054G>A	p.Asp352Asn	missense	Exon 5 of 6	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183515 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: 0.0000625

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098268 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363622

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40534

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842148

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

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.25
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.92	P
Vest4		0.69
MVP		0.62
MPC		2.1
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.41
gMVP		0.91
Mutation Taster		=65/35	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: rs1412018300; hg19: chrX-5821665; COSMIC: COSV52035862; COSMIC: COSV52035862;