14-78651233-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001330195.2(NRXN3):c.1128C>A(p.Gly376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,028 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (16 hom.)
• Consequence: NRXN3 NM_001330195.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 14-78651233-C-A is Benign according to our data. Variant chr14-78651233-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 778516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-78651233-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.182 with no splicing effect.
• BS2: High AC in GnomAd at 427 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN3	NM_001330195.2	c.1128C>A	p.Gly376=	synonymous_variant	6/21	ENST00000335750.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN3	ENST00000335750.7	c.1128C>A	p.Gly376=	synonymous_variant	6/21	5	NM_001330195.2	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00275 AC: 692 AN: 251398 Hom.: 2 AF XY: 0.00289 AC XY: 392 AN XY: 135868

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00274 AC: 4003 AN: 1461816 Hom.: 16 Cov.: 31 AF XY: 0.00277 AC XY: 2013 AN XY: 727208

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.00281 AC: 427 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74422

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00329

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00475

EpiControl AF: 0.00747

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NRXN3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	7.9
Dann	Benign	0.69

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: rs145345072; hg19: chr14-79117576;