rs5961397

Variant names:

• chrX-6004425-A-G
• rs5961397
• NM_181332.3:c.625+24855T>C

Variant summary

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

The NM_181332.3(NLGN4X):​c.625+24855T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 111,077 control chromosomes in the GnomAD database, including 3,827 homozygotes. There are 9,004 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 0.28 (3827 hom., 9004 hem., cov: 23)
• Consequence: NLGN4X NM_181332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 5 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.625+24855T>C		intron	N/A	NP_851849.1	Q8N0W4-1
	NLGN4X	NM_001282145.2		c.625+24855T>C		intron	N/A	NP_001269074.1	Q8N0W4-1
	NLGN4X	NM_001282146.2		c.625+24855T>C		intron	N/A	NP_001269075.1	Q8N0W4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.625+24855T>C		intron	N/A	ENSP00000370485.3	Q8N0W4-1
	NLGN4X	ENST00000538097.6	TSL:1	c.685+24855T>C		intron	N/A	ENSP00000439203.3	Q8N0W4-2
	NLGN4X	ENST00000275857.10	TSL:1	c.625+24855T>C		intron	N/A	ENSP00000275857.6	Q8N0W4-1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 30953 AN: 111021 Hom.: 3819 Cov.: 23

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.292

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.279 AC: 31005 AN: 111077 Hom.: 3827 Cov.: 23 AF XY: 0.270 AC XY: 9004 AN XY: 33319

African (AFR) AF: 0.488 AC: 14872 AN: 30481

American (AMR) AF: 0.237 AC: 2481 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 464 AN: 2638

East Asian (EAS) AF: 0.266 AC: 925 AN: 3482

South Asian (SAS) AF: 0.201 AC: 533 AN: 2648

European-Finnish (FIN) AF: 0.165 AC: 988 AN: 5978

Middle Eastern (MID) AF: 0.187 AC: 40 AN: 214

European-Non Finnish (NFE) AF: 0.191 AC: 10139 AN: 52970

Other (OTH) AF: 0.293 AC: 444 AN: 1514

Alfa AF: 0.230 Hom.: 1696

Bravo AF: 0.296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.22
DANN	Benign	0.49
PhyloP100		-2.6
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5961397;

hg19: chrX-5922466;