X-71147971-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_181303.2(NLGN3):c.222C>T(p.Tyr74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000556 in 1,205,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000049 (0 hom. 14 hem.)
• Consequence: NLGN3 NM_181303.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.366

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-71147971-C-T is Benign according to our data. Variant chrX-71147971-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1788074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.366 with no splicing effect.
• 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.222C>T	p.Tyr74=	synonymous_variant	2/8	ENST00000358741.4
LOC124905197	XR_007068262.1	n.1106+2312G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN3	ENST00000358741.4	c.222C>T	p.Tyr74=	synonymous_variant	2/8	5	NM_181303.2	A1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111320 Hom.: 0 Cov.: 22 AF XY: 0.000149 AC XY: 5 AN XY: 33482

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000382

Gnomad FIN AF: 0.000829

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000567

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 10 AN: 179349 Hom.: 0 AF XY: 0.0000467 AC XY: 3 AN XY: 64231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000540

Gnomad FIN exome AF: 0.000385

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000494 AC: 54 AN: 1094124 Hom.: 0 Cov.: 31 AF XY: 0.0000389 AC XY: 14 AN XY: 359734

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000743

Gnomad4 FIN exome AF: 0.000346

Gnomad4 NFE exome AF: 0.0000393

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111371 Hom.: 0 Cov.: 22 AF XY: 0.000149 AC XY: 5 AN XY: 33543

Gnomad4 AFR AF: 0.0000979

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000383

Gnomad4 FIN AF: 0.000829

Gnomad4 NFE AF: 0.0000567

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 1

Bravo AF: 0.0000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2019

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.58
Cadd	Benign	4.3
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs566418236; hg19: chrX-70367821;