chrX-5892908-G-A

Variant names:

• chrX-5892908-G-A
• rs4995611
• NM_181332.3:c.2360C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_181332.3(NLGN4X):​c.2360C>T​(p.Thr787Met) variant causes a missense change. The variant allele was found at a frequency of 0.000241 in 1,209,295 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T787T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00025 (0 hom. 92 hem.)
• Consequence: NLGN4X NM_181332.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.23
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047440022).
• BP6: Variant X-5892908-G-A is Benign according to our data. Variant chrX-5892908-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211681.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

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.2360C>T	p.Thr787Met	missense	Exon 6 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.2360C>T	p.Thr787Met	missense	Exon 7 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.2360C>T	p.Thr787Met	missense	Exon 6 of 6	NP_001269075.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.2360C>T	p.Thr787Met	missense	Exon 6 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.2420C>T	p.Thr807Met	missense	Exon 6 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.2360C>T	p.Thr787Met	missense	Exon 6 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 18 AN: 111005 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000218 AC: 40 AN: 183527 AF XY: 0.000250

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000249 AC: 274 AN: 1098233 Hom.: 0 Cov.: 32 AF XY: 0.000253 AC XY: 92 AN XY: 363591

African (AFR) AF: 0.000151 AC: 4 AN: 26403

American (AMR) AF: 0.000142 AC: 5 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000304 AC: 256 AN: 842117

Other (OTH) AF: 0.000174 AC: 8 AN: 46097

GnomAD4 genome AF: 0.000162 AC: 18 AN: 111062 Hom.: 0 Cov.: 22 AF XY: 0.000210 AC XY: 7 AN XY: 33278

African (AFR) AF: 0.0000328 AC: 1 AN: 30524

American (AMR) AF: 0.000192 AC: 2 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 53020

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.000254 Hom.: 3

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autism, susceptibility to, X-linked 2 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.025
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.0020	B
Vest4		0.18
MVP		0.27
MPC		1.1
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.062
gMVP		0.45
Mutation Taster		=100/0	polymorphism

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: rs4995611; hg19: chrX-5810949; COSMIC: COSV52025357;