NM_181332.3:c.*284G>A

Variant names:

• chrX-5892533-C-T
• rs3810686
• NM_181332.3:c.*284G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181332.3(NLGN4X):​c.*284G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 331,094 control chromosomes in the GnomAD database, including 18,698 homozygotes. There are 38,258 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (4931 hom., 10746 hem., cov: 23)
  • Exomes 𝑓: 0.41 (13767 hom. 27512 hem.)
• Consequence: NLGN4X NM_181332.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00700
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.*284G>A		3_prime_UTR_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.*284G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes AF: 0.319 AC: 35416 AN: 110912 Hom.: 4932 Cov.: 23

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.412 AC: 90738 AN: 220126 Hom.: 13767 Cov.: 2 AF XY: 0.419 AC XY: 27512 AN XY: 65596

African (AFR) AF: 0.0747 AC: 541 AN: 7242

American (AMR) AF: 0.362 AC: 3957 AN: 10935

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 2711 AN: 6427

East Asian (EAS) AF: 0.616 AC: 8282 AN: 13452

South Asian (SAS) AF: 0.441 AC: 9876 AN: 22388

European-Finnish (FIN) AF: 0.438 AC: 5063 AN: 11564

Middle Eastern (MID) AF: 0.451 AC: 400 AN: 887

European-Non Finnish (NFE) AF: 0.409 AC: 54834 AN: 134175

Other (OTH) AF: 0.389 AC: 5074 AN: 13056

GnomAD4 genome AF: 0.319 AC: 35410 AN: 110968 Hom.: 4931 Cov.: 23 AF XY: 0.324 AC XY: 10746 AN XY: 33216

African (AFR) AF: 0.0738 AC: 2263 AN: 30673

American (AMR) AF: 0.339 AC: 3547 AN: 10460

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1132 AN: 2644

East Asian (EAS) AF: 0.619 AC: 2164 AN: 3497

South Asian (SAS) AF: 0.445 AC: 1158 AN: 2600

European-Finnish (FIN) AF: 0.457 AC: 2669 AN: 5835

Middle Eastern (MID) AF: 0.565 AC: 122 AN: 216

European-Non Finnish (NFE) AF: 0.411 AC: 21724 AN: 52854

Other (OTH) AF: 0.327 AC: 495 AN: 1516

Alfa AF: 0.375 Hom.: 45347

Bravo AF: 0.303

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.23
DANN	Benign	0.51
PhyloP100		-0.0070
Mutation Taster		=100/0	polymorphism (auto)

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: rs3810686; hg19: chrX-5810574;