X-5892971-C-T

Variant names:

• chrX-5892971-C-T
• rs1445553567
• NM_181332.3:c.2297G>A

Variant summary

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

The NM_181332.3(NLGN4X):​c.2297G>A​(p.Arg766Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,209,322 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.2297G>A	p.Arg766Gln	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.2297G>A	p.Arg766Gln	missense_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111053 Hom.: 0 Cov.: 22

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098269 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363623

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: 0.00 AC: 0 AN: 40534

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

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 842149

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

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111053 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33257

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

African (AFR) AF: 0.00 AC: 0 AN: 30473

American (AMR) AF: 0.00 AC: 0 AN: 10418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00 AC: 0 AN: 2574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53011

Other (OTH) AF: 0.00 AC: 0 AN: 1496

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;D;D;.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	.;D;.;D;.
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;M;M;.;M
PhyloP100		6.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;.;D;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.014	D;D;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.40
MVP		0.63
MPC		2.2
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.43
gMVP		0.74
Mutation Taster		=86/14	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: rs1445553567; hg19: chrX-5811012; COSMIC: COSV99319743;