Variant X-71147990-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_181303.2(NLGN3):c.241G>A(p.Glu81Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,205,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

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: 9.60

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2 linkuse as main transcript	c.241G>A	p.Glu81Lys	missense_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1 linkuse as main transcript	n.1106+2293C>T		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.241G>A	p.Glu81Lys	missense_variant	2/8	5	NM_181303.2	A1	Q9NZ94-1

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

110949

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33167

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181299

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

66005

show subpopulations

Gnomad AFR exome

AF:

0.0000768

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1094994

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360630

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:

0.00000901

AC:

AN:

110949

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33167

show subpopulations

Gnomad4 AFR

AF:

0.0000329

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

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 14, 2021

The c.241G>A (p.E81K) alteration is located in exon 2 (coding exon 1) of the NLGN3 gene. This alteration results from a G to A substitution at nucleotide position 241, causing the glutamic acid (E) at amino acid position 81 to be replaced by a lysine (K). 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

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

.;.;.;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.070

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.72

N;.;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.4

N;D;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.37

T;T;T;T

Polyphen

0.56

.;.;P;.

Vest4

0.46

MutPred

0.62

Gain of methylation at E81 (P = 0.0013);Gain of methylation at E81 (P = 0.0013);Gain of methylation at E81 (P = 0.0013);Gain of methylation at E81 (P = 0.0013);

MVP

0.78

MPC

1.6

ClinPred

0.42

GERP RS

4.4

Varity_R

0.70

gMVP

0.71

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