14-78714883-C-T

Variant names:

• chr14-78714883-C-T
• rs1004212
• NM_001330195.2:c.1788C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001330195.2(NRXN3):​c.1788C>T​(p.Thr596Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,614,000 control chromosomes in the GnomAD database, including 20,840 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 0.19 (3112 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17728 hom.)
• Consequence: NRXN3 NM_001330195.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.38
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-4.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN3	NM_001330195.2	c.1788C>T	p.Thr596Thr	synonymous_variant	Exon 8 of 21	ENST00000335750.7	NP_001317124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN3	ENST00000335750.7	c.1788C>T	p.Thr596Thr	synonymous_variant	Exon 8 of 21	5	NM_001330195.2	ENSP00000338349.7

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28118 AN: 152046 Hom.: 3104 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0688

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.155 AC: 38875 AN: 251168 AF XY: 0.161

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.0688

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0702

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.147 AC: 214196 AN: 1461834 Hom.: 17728 Cov.: 35 AF XY: 0.151 AC XY: 109466 AN XY: 727218

African (AFR) AF: 0.308 AC: 10303 AN: 33480

American (AMR) AF: 0.0733 AC: 3279 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5359 AN: 26136

East Asian (EAS) AF: 0.0687 AC: 2726 AN: 39686

South Asian (SAS) AF: 0.265 AC: 22897 AN: 86256

European-Finnish (FIN) AF: 0.110 AC: 5893 AN: 53414

Middle Eastern (MID) AF: 0.189 AC: 1089 AN: 5768

European-Non Finnish (NFE) AF: 0.138 AC: 153081 AN: 1111976

Other (OTH) AF: 0.158 AC: 9569 AN: 60394

GnomAD4 genome AF: 0.185 AC: 28171 AN: 152166 Hom.: 3112 Cov.: 32 AF XY: 0.184 AC XY: 13671 AN XY: 74380

African (AFR) AF: 0.301 AC: 12512 AN: 41506

American (AMR) AF: 0.114 AC: 1747 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3468

East Asian (EAS) AF: 0.0691 AC: 356 AN: 5150

South Asian (SAS) AF: 0.274 AC: 1324 AN: 4828

European-Finnish (FIN) AF: 0.107 AC: 1133 AN: 10596

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9823 AN: 68008

Other (OTH) AF: 0.181 AC: 382 AN: 2116

Alfa AF: 0.156 Hom.: 3434

Bravo AF: 0.185

Asia WGS AF: 0.169 AC: 587 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.42
DANN	Benign	0.87
PhyloP100		-4.4
Mutation Taster		=99/1	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: rs1004212; hg19: chr14-79181226; COSMIC: COSV59752848; COSMIC: COSV59752848;