X-71147986-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_181303.2(NLGN3):c.237C>G(p.Ile79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,235 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.425

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 2 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=0.4150126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN3	NM_181303.2	c.237C>G	p.Ile79Met	missense_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1	n.1106+2297G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4	c.237C>G	p.Ile79Met	missense_variant	2/8	5	NM_181303.2	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000553 AC: 1 AN: 180763 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65495

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

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: 9.14e-7 AC: 1 AN: 1094235 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359865

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 20, 2023

Variant summary: NLGN3 c.237C>G (p.Ile79Met) results in a conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 180763 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.237C>G in individuals affected with Autism Susceptibility, X-Linked and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	D;D;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.91	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.037	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.54	.;.;P;.
Vest4		0.35
MutPred		0.74		Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);
MVP		0.68
MPC		1.3
ClinPred		0.62	D
GERP RS		2.4
Varity_R		0.40
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

Other links and lift over

dbSNP: rs756256945; hg19: chrX-70367836;