X-71147842-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_181303.2(NLGN3):c.93G>C(p.Leu31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NLGN3
• BP4: Computational evidence support a benign effect (MetaRNN=0.22414586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2	c.93G>C	p.Leu31Phe	missense_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1	n.1106+2441C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4	c.93G>C	p.Leu31Phe	missense_variant	2/8	5	NM_181303.2	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000573 AC: 1 AN: 174375 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000372

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 AF: 0.00000183 AC: 2 AN: 1094772 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000572

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	16
Dann	Benign	0.92
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.96	L;.;L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.072
MutPred		0.67		Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);Gain of methylation at R34 (P = 0.1122);
MVP		0.59
MPC		0.74
ClinPred		0.084	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.23

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: rs1258826819; hg19: chrX-70367692;