dbSNP rs886042929: NLGN4X:p.Arg753Ser (chrX-5893009-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_181332.3(NLGN4X):c.2259G>T(p.Arg753Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 21)

Consequence

NLGN4X
NM_181332.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.598

Publications

2 publications found

Variant links:

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)

NLGN4X links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLGN4X	NM_181332.3	MANE Select	c.2259G>T	p.Arg753Ser	missense	Exon 6 of 6	NP_851849.1	Q8N0W4-1
NLGN4X	NM_001282145.2		c.2259G>T	p.Arg753Ser	missense	Exon 7 of 7	NP_001269074.1	Q8N0W4-1
NLGN4X	NM_001282146.2		c.2259G>T	p.Arg753Ser	missense	Exon 6 of 6	NP_001269075.1	Q8N0W4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.2259G>T	p.Arg753Ser	missense	Exon 6 of 6	ENSP00000370485.3	Q8N0W4-1
NLGN4X	ENST00000538097.6	TSL:1	c.2319G>T	p.Arg773Ser	missense	Exon 6 of 6	ENSP00000439203.3	Q8N0W4-2
NLGN4X	ENST00000275857.10	TSL:1	c.2259G>T	p.Arg753Ser	missense	Exon 6 of 6	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

FATHMM_MKL

Benign

0.59

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

0.60

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.96

Vest4

0.52

MVP

0.79

MPC

2.2

ClinPred

0.98

GERP RS

2.8

Varity_R

0.46

gMVP

0.76

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over