X-71147978-C-T

Position:

chrX-71147978-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_181303.2(NLGN3):c.229C>T(p.Pro77Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000332 in 1,206,055 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Variant links:

Genes affected

NLGN3 (HGNC:14289): (neuroligin 3) This gene encodes a member of 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. Mutations in this gene may be associated with autism and Asperger syndrome. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Oct 2009]

NLGN3 links:

LOC124905197 (HGNC:):

LOC124905197 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLGN3. . Gene score misZ 4.206 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked complex neurodevelopmental disorder, autism, susceptibility to, X-linked 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2 linkuse as main transcript	c.229C>T	p.Pro77Ser	missense_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1 linkuse as main transcript	n.1106+2305G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4 linkuse as main transcript	c.229C>T	p.Pro77Ser	missense_variant	2/8	5	NM_181303.2	A1	Q9NZ94-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111152

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33348

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180067

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64875

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1094903

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360499

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111152

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2018

The p.P77S variant (also known as c.229C>T), located in coding exon 1 of the NLGN3 gene, results from a C to T substitution at nucleotide position 229. The proline at codon 77 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;.;.;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.4

M;.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Uncertain

0.055

T;D;T;T

Polyphen

0.50

.;.;P;.

Vest4

0.57

MutPred

0.87

Gain of glycosylation at P77 (P = 0.0527);Gain of glycosylation at P77 (P = 0.0527);Gain of glycosylation at P77 (P = 0.0527);Gain of glycosylation at P77 (P = 0.0527);

MVP

0.78

MPC

1.0

ClinPred

0.51

GERP RS

3.9

Varity_R

0.49

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over