X-5893491-G-C

Position:

• chrX-5893491-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181332.3(NLGN4X):​c.1777C>G​(p.Leu593Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L593F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 20)
  • Failed GnomAD Quality Control
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN4X	NM_181332.3	c.1777C>G	p.Leu593Val	missense_variant	6/6	ENST00000381095.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN4X	ENST00000381095.8	c.1777C>G	p.Leu593Val	missense_variant	6/6	1	NM_181332.3	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 107976 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 30726 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 107976 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 30726

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000259 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T;.;T
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.9	M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;.;N;.;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.058	T;T;T;.;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.50
MVP		0.81
MPC		2.1
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.56
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs3747333; hg19: chrX-5811532;