X-5893140-G-T

Variant names:

• chrX-5893140-G-T
• rs763458960
• NM_181332.3:c.2128C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181332.3(NLGN4X):​c.2128C>A​(p.Arg710Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R710H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24478325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.2128C>A	p.Arg710Ser	missense_variant	Exon 6 of 6	ENST00000381095.8	NP_851849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8	c.2128C>A	p.Arg710Ser	missense_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R710S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R710S variant is not observed in large population cohorts (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.46	T;T;T;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;.;D;.
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	L;L;L;.;L
PhyloP100		5.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D;.;D;.;D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;.;D;.;D
Sift4G	Uncertain	0.030	D;D;D;.;D
Polyphen		0.042	B;B;B;B;B
Vest4		0.38
MutPred		0.24		Gain of phosphorylation at R710 (P = 0.0261);Gain of phosphorylation at R710 (P = 0.0261);Gain of phosphorylation at R710 (P = 0.0261);.;Gain of phosphorylation at R710 (P = 0.0261);
MVP		0.63
MPC		2.2
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.34
gMVP		0.71
Mutation Taster		=88/12	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: rs763458960; hg19: chrX-5811181; COSMIC: COSV52036801;