dbSNP rs2290488: NLGN4X:c.-431G>C (chrX-6227814-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000275857.10(NLGN4X):c.-431G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 109,188 control chromosomes in the GnomAD database, including 3,992 homozygotes. There are 9,433 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 0.30 ( 3983 hom., 9424 hem., cov: 21)

Exomes 𝑓: 0.35 ( 9 hom. 9 hem. )

Consequence

NLGN4X
ENST00000275857.10 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0590

Publications

6 publications found

Variant links:

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

NLGN4X links:

LOC105373156 (HGNC:):

LOC105373156 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN4X	NM_181332.3 link	c.-306+727G>C		intron_variant	Intron 1 of 5	ENST00000381095.8	NP_851849.1	Q8N0W4-1A0A024RBV0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLGN4X	ENST00000275857.10 link	c.-431G>C	5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000275857.6	Q8N0W4-1
NLGN4X	ENST00000381095.8 link	c.-306+727G>C	intron_variant	Intron 1 of 5	1	NM_181332.3	ENSP00000370485.3	Q8N0W4-1
NLGN4X	ENST00000381092.1 link	c.-613+727G>C	intron_variant	Intron 1 of 6	2		ENSP00000370482.1	Q8N0W4-1

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

32807

AN:

108983

Hom.:

3984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.394

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.311

Gnomad NFE

AF:

0.371

Gnomad OTH

AF:

0.312

GnomAD4 exome

AF:

0.355

AC:

AN:

155

Hom.:

Cov.:

AF XY:

0.243

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.571

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.330

AC:

AN:

106

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.301

AC:

32825

AN:

109033

Hom.:

3983

Cov.:

AF XY:

0.300

AC XY:

9424

AN XY:

31455

show subpopulations

African (AFR)

AF:

0.140

AC:

4200

AN:

29979

American (AMR)

AF:

0.368

AC:

3787

AN:

10287

Ashkenazi Jewish (ASJ)

AF:

0.394

AC:

1029

AN:

2614

East Asian (EAS)

AF:

0.205

AC:

698

AN:

3413

South Asian (SAS)

AF:

0.342

AC:

835

AN:

2445

European-Finnish (FIN)

AF:

0.380

AC:

2131

AN:

5609

Middle Eastern (MID)

AF:

0.315

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.371

AC:

19406

AN:

52336

Other (OTH)

AF:

0.318

AC:

470

AN:

1477

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

800

1600

2400

3200

4000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.315

Hom.:

2028

Bravo

AF:

0.293

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.25

(source)

DANN

Benign

0.63

PhyloP100

-0.059

PromoterAI

-0.015

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over