Variant X-71147819-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_181303.2(NLGN3):c.70C>T(p.Leu24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,987 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Consequence

NLGN3
NM_181303.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

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:

NLGN3 (HGNC:):

NLGN3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09091583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLGN3	NM_181303.2 linkuse as main transcript	c.70C>T	p.Leu24Phe	missense_variant	2/8	ENST00000358741.4	NP_851820.1	Q9NZ94-1X5DNV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4 linkuse as main transcript	c.70C>T	p.Leu24Phe	missense_variant	2/8	5	NM_181303.2	ENSP00000351591.4		Q9NZ94-1
NLGN3	ENST00000685718.1 linkuse as main transcript	n.70C>T		non_coding_transcript_exon_variant	2/8			ENSP00000510514.1		A0A8I5QJU7

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111934

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34080

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000565

AC:

AN:

176976

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000370

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34143

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

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

Jul 30, 2024

The c.70C>T (p.L24F) alteration is located in exon 2 (coding exon 1) of the NLGN3 gene. This alteration results from a C to T substitution at nucleotide position 70, causing the leucine (L) at amino acid position 24 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;.;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.091

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.3

L;.;L;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.82

N;N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Benign

0.073

T;D;T;T

Polyphen

0.0010

.;.;B;.

Vest4

0.19

MutPred

0.73

Loss of catalytic residue at L24 (P = 0.0665);Loss of catalytic residue at L24 (P = 0.0665);Loss of catalytic residue at L24 (P = 0.0665);Loss of catalytic residue at L24 (P = 0.0665);

MVP

0.68

MPC

0.75

ClinPred

0.19

GERP RS

3.7

Varity_R

0.24

gMVP

0.36

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