X-5903545-T-C

Variant names:

• chrX-5903545-T-C
• rs144093574
• NM_181332.3:c.1133A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020742.4(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. 13/21 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 NM_020742.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.21
• Publications: 11 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 -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 Benign/Likely_benign. ClinVar VariationId is 587836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	NM_181332.3	MANE Select	c.1133A>G	p.Lys378Arg	missense	Exon 5 of 6	NP_851849.1
	NLGN4X	NM_001282145.2		c.1133A>G	p.Lys378Arg	missense	Exon 6 of 7	NP_001269074.1
	NLGN4X	NM_001282146.2		c.1133A>G	p.Lys378Arg	missense	Exon 5 of 6	NP_001269075.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.1133A>G	p.Lys378Arg	missense	Exon 5 of 6	ENSP00000370485.3
	NLGN4X	ENST00000538097.6	TSL:1	c.1193A>G	p.Lys398Arg	missense	Exon 5 of 6	ENSP00000439203.3
	NLGN4X	ENST00000275857.10	TSL:1	c.1133A>G	p.Lys378Arg	missense	Exon 5 of 6	ENSP00000275857.6

Frequencies

GnomAD3 genomes AF: 0.000281 AC: 31 AN: 110346 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.000296 AC: 53 AN: 178855 AF XY: 0.000327

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 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

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.000142 AC: 5 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.000469 AC: 19 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000336 AC: 283 AN: 841850

Other (OTH) AF: 0.000260 AC: 12 AN: 46079

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

African (AFR) AF: 0.0000330 AC: 1 AN: 30290

American (AMR) AF: 0.0000954 AC: 1 AN: 10483

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.00 AC: 0 AN: 2472

European-Finnish (FIN) AF: 0.000672 AC: 4 AN: 5953

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000456 AC: 24 AN: 52670

Other (OTH) AF: 0.000666 AC: 1 AN: 1501

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.045	N
PhyloP100		5.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.088
Sift	Benign	0.26	T
Sift4G	Benign	0.61	T
Polyphen		0.018	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
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: rs144093574; hg19: chrX-5821586; COSMIC: COSV99320062; COSMIC: COSV99320062;