X-5892715-C-T

Variant names:

• chrX-5892715-C-T
• rs3810688
• NM_181332.3:c.*102G>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.*102G>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 0.315 in 1,112,611 control chromosomes in the GnomAD database, including 41,117 homozygotes. There are 106,097 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 0.38 (6558 hom., 11781 hem., cov: 22)
  • Exomes 𝑓: 0.31 (34559 hom. 94316 hem.)
• Consequence: NLGN4X NM_181332.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.452
• Publications: 8 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) 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.*102G>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.*102G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 41590 AN: 110091 Hom.: 6558 Cov.: 22

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.308 AC: 309113 AN: 1002466 Hom.: 34559 Cov.: 19 AF XY: 0.311 AC XY: 94316 AN XY: 302982

African (AFR) AF: 0.616 AC: 14991 AN: 24338

American (AMR) AF: 0.280 AC: 8208 AN: 29331

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 5557 AN: 17954

East Asian (EAS) AF: 0.145 AC: 4084 AN: 28201

South Asian (SAS) AF: 0.261 AC: 12532 AN: 48041

European-Finnish (FIN) AF: 0.276 AC: 9409 AN: 34089

Middle Eastern (MID) AF: 0.238 AC: 928 AN: 3903

European-Non Finnish (NFE) AF: 0.310 AC: 240220 AN: 773743

Other (OTH) AF: 0.308 AC: 13184 AN: 42866

GnomAD4 genome AF: 0.378 AC: 41630 AN: 110145 Hom.: 6558 Cov.: 22 AF XY: 0.363 AC XY: 11781 AN XY: 32451

African (AFR) AF: 0.604 AC: 18177 AN: 30079

American (AMR) AF: 0.316 AC: 3280 AN: 10384

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 806 AN: 2627

East Asian (EAS) AF: 0.143 AC: 497 AN: 3481

South Asian (SAS) AF: 0.246 AC: 633 AN: 2576

European-Finnish (FIN) AF: 0.256 AC: 1506 AN: 5880

Middle Eastern (MID) AF: 0.204 AC: 44 AN: 216

European-Non Finnish (NFE) AF: 0.302 AC: 15918 AN: 52738

Other (OTH) AF: 0.339 AC: 505 AN: 1490

Alfa AF: 0.329 Hom.: 2075

Bravo AF: 0.392

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	-0.97
CADD	Benign	0.077
DANN	Benign	0.52
PhyloP100		-0.45
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: rs3810688; hg19: chrX-5810756; COSMIC: COSV52009610;