X-71147759-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_181303.2(NLGN3):c.10C>T(p.Arg4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,203,792 control chromosomes in the GnomAD database, including 2 homozygotes. There are 154 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00032 (2 hom. 149 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.547

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]

LOC124905197 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NLGN3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0065551996).
• BP6: Variant X-71147759-C-T is Benign according to our data. Variant chrX-71147759-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425503.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2	c.10C>T	p.Arg4Trp	missense_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1	n.1106+2524G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4	c.10C>T	p.Arg4Trp	missense_variant	2/8	5	NM_181303.2	A1

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 18 AN: 111878 Hom.: 0 Cov.: 22 AF XY: 0.000147 AC XY: 5 AN XY: 34054

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: 0.00444

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000718 AC: 120 AN: 167141 Hom.: 2 AF XY: 0.000806 AC XY: 46 AN XY: 57095

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00623

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000681

Gnomad OTH exome AF: 0.000480

GnomAD4 exome AF: 0.000323 AC: 353 AN: 1091862 Hom.: 2 Cov.: 31 AF XY: 0.000416 AC XY: 149 AN XY: 358604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000862

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00461

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000762

Gnomad4 OTH exome AF: 0.000677

GnomAD4 genome AF: 0.000152 AC: 17 AN: 111930 Hom.: 0 Cov.: 22 AF XY: 0.000147 AC XY: 5 AN XY: 34114

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00408

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000152 AC: 1

ExAC AF: 0.000772 AC: 93

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 06, 2018

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Benign	0.96
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.19	T;T;T;T
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		0.0020	.;.;B;.
Vest4		0.21
MVP		0.74
MPC		0.76
ClinPred		0.052	T
GERP RS		1.6
Varity_R		0.076
gMVP		0.59

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

Other links and lift over

dbSNP: rs376877146; hg19: chrX-70367609;