rs4899727

Variant names:

• chr14-78858510-A-G
• rs4899727
• NM_001330195.2:c.2275+48166A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330195.2(NRXN3):​c.2275+48166A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 152,272 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.046 (334 hom., cov: 32)
• Consequence: NRXN3 NM_001330195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• Publications: 3 publications found

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]

NRXN3 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330195.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	NM_001330195.2	MANE Select	c.2275+48166A>G		intron	N/A	NP_001317124.1
	NRXN3	NM_001366425.1		c.2275+48166A>G		intron	N/A	NP_001353354.1
	NRXN3	NM_001366426.1		c.2287+48166A>G		intron	N/A	NP_001353355.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.2275+48166A>G		intron	N/A	ENSP00000338349.7
	NRXN3	ENST00000554719.5	TSL:1	c.1156+48166A>G		intron	N/A	ENSP00000451648.1
	NRXN3	ENST00000556496.2	TSL:1	n.1592+54687A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6924 AN: 152154 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0487

Gnomad OTH AF: 0.0340

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0456 AC: 6939 AN: 152272 Hom.: 334 Cov.: 32 AF XY: 0.0457 AC XY: 3403 AN XY: 74454

African (AFR) AF: 0.0122 AC: 506 AN: 41562

American (AMR) AF: 0.161 AC: 2451 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4830

European-Finnish (FIN) AF: 0.0232 AC: 247 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0487 AC: 3309 AN: 68014

Other (OTH) AF: 0.0331 AC: 70 AN: 2112

Alfa AF: 0.0497 Hom.: 124

Bravo AF: 0.0531

Asia WGS AF: 0.0230 AC: 78 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.069
DANN	Benign	0.68
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4899727; hg19: chr14-79324853;