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 NM_020742.4(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
NM_020742.4 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NLGN4X	NM_181332.3	MANE Select	c.-306+727G>C	intron	N/A	NP_851849.1	Q8N0W4-1
NLGN4X	NM_020742.4		c.-431G>C	5_prime_UTR	Exon 1 of 6	NP_065793.1	Q8N0W4-1
NLGN4X	NM_001282145.2		c.-613+727G>C	intron	N/A	NP_001269074.1	Q8N0W4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NLGN4X	ENST00000275857.10	TSL:1	c.-431G>C	5_prime_UTR	Exon 1 of 6	ENSP00000275857.6	Q8N0W4-1
NLGN4X	ENST00000381095.8	TSL:1 MANE Select	c.-306+727G>C	intron	N/A	ENSP00000370485.3	Q8N0W4-1
NLGN4X	ENST00000381092.1	TSL:2	c.-613+727G>C	intron	N/A	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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over