X-5892840-C-T

Position:

• chrX-5892840-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_181332.3(NLGN4X):​c.2428G>A​(p.Gly810Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,098,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.05

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN4X	NM_181332.3	c.2428G>A	p.Gly810Arg	missense_variant	6/6	ENST00000381095.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN4X	ENST00000381095.8	c.2428G>A	p.Gly810Arg	missense_variant	6/6	1	NM_181332.3	P4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098184 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autism, susceptibility to, X-linked 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 16, 2022	This NLGN4X variant is absent from a large population dataset and has been reported in ClinVar. Of three bioinformatics tools queried, one predicts that the substitution would be damaging, while two predict that it would be tolerated. The glycine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 6 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence, we consider the clinical significance of c.2428G>A to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory de novo in a 6-year-old female with autism, intellectual disability, hypotonia, dysmorphism, short fingers, clinodactyly, overlapping toes, widely spaced nipples, hyperextensibility -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;.;T
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.1	L;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;.;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.039	D;.;D;.;D
Sift4G	Benign	0.20	T;T;T;.;T
Polyphen		0.86	P;P;P;P;P
Vest4		0.42
MVP		0.65
MPC		2.3
ClinPred		0.74	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.49

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: rs1181689310; hg19: chrX-5810881; COSMIC: COSV52025924;