X-5892643-G-T

Variant names:

• chrX-5892643-G-T
• rs3810687
• NM_181332.3:c.*174C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181332.3(NLGN4X):​c.*174C>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 0.111 in 567,548 control chromosomes in the GnomAD database, including 2,585 homozygotes. There are 18,925 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (543 hom., 3441 hem., cov: 23)
  • Exomes 𝑓: 0.11 (2042 hom. 15484 hem.)
• Consequence: NLGN4X NM_181332.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.08
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-5892643-G-T is Benign according to our data. Variant chrX-5892643-G-T is described in ClinVar as [Benign]. Clinvar id is 1266217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.*174C>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.*174C>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_181332.3	ENSP00000370485.3

Frequencies

GnomAD3 genomes AF: 0.109 AC: 12070 AN: 111086 Hom.: 542 Cov.: 23

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0880

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.112 AC: 51083 AN: 456406 Hom.: 2042 Cov.: 7 AF XY: 0.114 AC XY: 15484 AN XY: 135784

African (AFR) AF: 0.119 AC: 1526 AN: 12870

American (AMR) AF: 0.0496 AC: 1022 AN: 20585

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 1027 AN: 11798

East Asian (EAS) AF: 0.123 AC: 2939 AN: 23873

South Asian (SAS) AF: 0.0915 AC: 2866 AN: 31308

European-Finnish (FIN) AF: 0.107 AC: 2549 AN: 23883

Middle Eastern (MID) AF: 0.136 AC: 261 AN: 1923

European-Non Finnish (NFE) AF: 0.118 AC: 36193 AN: 305947

Other (OTH) AF: 0.111 AC: 2700 AN: 24219

GnomAD4 genome AF: 0.109 AC: 12085 AN: 111142 Hom.: 543 Cov.: 23 AF XY: 0.103 AC XY: 3441 AN XY: 33366

African (AFR) AF: 0.116 AC: 3534 AN: 30550

American (AMR) AF: 0.0735 AC: 770 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 213 AN: 2649

East Asian (EAS) AF: 0.117 AC: 411 AN: 3501

South Asian (SAS) AF: 0.0867 AC: 225 AN: 2596

European-Finnish (FIN) AF: 0.0981 AC: 586 AN: 5976

Middle Eastern (MID) AF: 0.120 AC: 26 AN: 216

European-Non Finnish (NFE) AF: 0.114 AC: 6017 AN: 52988

Other (OTH) AF: 0.102 AC: 155 AN: 1514

Alfa AF: 0.110 Hom.: 5225

Bravo AF: 0.110

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	-0.79
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		2.1
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: rs3810687; hg19: chrX-5810684;