14-78243471-T-C

Position:

• chr14-78243471-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001330195.2(NRXN3):​c.378T>C​(p.Asp126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,583,006 control chromosomes in the GnomAD database, including 36,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2690 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34223 hom.)
• Consequence: NRXN3 NM_001330195.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

Genes affected

NRXN3 (HGNC:8010): (neurexin 3) This gene encodes a member of a family of proteins that function in the nervous system as receptors and cell adhesion molecules. Extensive alternative splicing and the use of alternative promoters results in multiple transcript variants and protein isoforms for this gene, but the full-length nature of many of these variants has not been determined. Transcripts that initiate from an upstream promoter encode alpha isoforms, which contain epidermal growth factor-like (EGF-like) sequences and laminin G domains. Transcripts initiating from the downstream promoter encode beta isoforms, which lack EGF-like sequences. Genetic variation at this locus has been associated with a range of behavioral phenotypes, including alcohol dependence and autism spectrum disorder. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-78243471-T-C is Benign according to our data. Variant chr14-78243471-T-C is described in ClinVar as [Benign]. Clinvar id is 674092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN3	NM_001330195.2	c.378T>C	p.Asp126=	synonymous_variant	2/21	ENST00000335750.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN3	ENST00000335750.7	c.378T>C	p.Asp126=	synonymous_variant	2/21	5	NM_001330195.2	P1
NRXN3	ENST00000634499.2	c.378T>C	p.Asp126=	synonymous_variant	2/22	5
NRXN3	ENST00000554738.5	c.378T>C	p.Asp126=	synonymous_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26519 AN: 152102 Hom.: 2688 Cov.: 32

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.195 AC: 39594 AN: 202706 Hom.: 4069 AF XY: 0.200 AC XY: 22426 AN XY: 111866

Gnomad AFR exome AF: 0.0743

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.0479

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.215 AC: 308096 AN: 1430788 Hom.: 34223 Cov.: 33 AF XY: 0.216 AC XY: 153638 AN XY: 710436

Gnomad4 AFR exome AF: 0.0705

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.0618

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.174 AC: 26530 AN: 152218 Hom.: 2690 Cov.: 32 AF XY: 0.174 AC XY: 12984 AN XY: 74418

Gnomad4 AFR AF: 0.0742

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.190

Alfa AF: 0.205 Hom.: 628

Bravo AF: 0.168

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.076
DANN	Benign	0.30

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: rs1882821; hg19: chr14-78709814;