X-5903545-T-C

Position:

• chrX-5903545-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000381095.8(NLGN4X):​c.1133A>G​(p.Lys378Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00029 in 1,208,306 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 117 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00029 (0 hom. 109 hem.)
• Consequence: NLGN4X ENST00000381095.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.21

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039590776).
• BP6: Variant X-5903545-T-C is Benign according to our data. Variant chrX-5903545-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 587836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN4X	NM_181332.3	c.1133A>G	p.Lys378Arg	missense_variant	5/6	ENST00000381095.8	NP_851849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN4X	ENST00000381095.8	c.1133A>G	p.Lys378Arg	missense_variant	5/6	1	NM_181332.3	ENSP00000370485	P4

Frequencies

GnomAD3 genomes AF: 0.000281 AC: 31 AN: 110346 Hom.: 0 Cov.: 22 AF XY: 0.000246 AC XY: 8 AN XY: 32544

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000672

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000675

GnomAD3 exomes AF: 0.000296 AC: 53 AN: 178855 Hom.: 0 AF XY: 0.000327 AC XY: 21 AN XY: 64183

Gnomad AFR exome AF: 0.0000784

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000639

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000452

GnomAD4 exome AF: 0.000291 AC: 320 AN: 1097909 Hom.: 0 Cov.: 32 AF XY: 0.000300 AC XY: 109 AN XY: 363297

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.000260

GnomAD4 genome AF: 0.000281 AC: 31 AN: 110397 Hom.: 0 Cov.: 22 AF XY: 0.000245 AC XY: 8 AN XY: 32605

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.0000954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000672

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000666

Alfa AF: 0.000383 Hom.: 3

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000449 AC: 3

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	NLGN4X: BS2 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T;.;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	.;D;.;D;.
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.040	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.045	N;N;N;.;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;.;N;.;N
REVEL	Benign	0.088
Sift	Benign	0.26	T;.;T;.;T
Sift4G	Benign	0.61	T;T;T;.;T
Polyphen		0.018	B;B;B;B;B
Vest4		0.38
MVP		0.51
MPC		1.0
ClinPred		0.035	T
GERP RS		3.9
Varity_R		0.28
gMVP		0.84

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: rs144093574; hg19: chrX-5821586; COSMIC: COSV99320062; COSMIC: COSV99320062;