X-71147975-G-A

Variant names:

• chrX-71147975-G-A
• rs2092376950
• NM_181303.2:c.226G>A

Variant summary

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

The NM_181303.2(NLGN3):​c.226G>A​(p.Ala76Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NLGN3 NM_181303.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.3631891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN3	NM_181303.2	c.226G>A	p.Ala76Thr	missense_variant	Exon 2 of 8	ENST00000358741.4	NP_851820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN3	ENST00000358741.4	c.226G>A	p.Ala76Thr	missense_variant	Exon 2 of 8	5	NM_181303.2	ENSP00000351591.4
NLGN3	ENST00000685718.1	n.226G>A		non_coding_transcript_exon_variant	Exon 2 of 8			ENSP00000510514.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1095093 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360641

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Alfa AF: 0.000187 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;.;.;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.63	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.22
MutPred		0.44		Gain of glycosylation at A76 (P = 0.0056);Gain of glycosylation at A76 (P = 0.0056);Gain of glycosylation at A76 (P = 0.0056);Gain of glycosylation at A76 (P = 0.0056);
MVP		0.70
MPC		0.73
ClinPred		0.38	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.64

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: rs2092376950; hg19: chrX-70367825;