14-78749467-T-G

Variant names:

• chr14-78749467-T-G
• rs725693
• NM_001330195.2:c.2044+34328T>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.2044+34328T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 152,000 control chromosomes in the GnomAD database, including 18,838 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 0.47 (18838 hom., cov: 32)
• Consequence: NRXN3 NM_001330195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652
• Publications: 5 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

ENSG00000258478 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN3	NM_001330195.2	c.2044+34328T>G		intron_variant	Intron 8 of 20	ENST00000335750.7	NP_001317124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN3	ENST00000335750.7	c.2044+34328T>G		intron_variant	Intron 8 of 20	5	NM_001330195.2	ENSP00000338349.7

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71644 AN: 151882 Hom.: 18808 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.473

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

GnomAD4 genome AF: 0.472 AC: 71718 AN: 152000 Hom.: 18838 Cov.: 32 AF XY: 0.469 AC XY: 34842 AN XY: 74278

African (AFR) AF: 0.703 AC: 29126 AN: 41452

American (AMR) AF: 0.320 AC: 4893 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1937 AN: 3470

East Asian (EAS) AF: 0.416 AC: 2148 AN: 5158

South Asian (SAS) AF: 0.534 AC: 2569 AN: 4808

European-Finnish (FIN) AF: 0.355 AC: 3747 AN: 10564

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25713 AN: 67974

Other (OTH) AF: 0.475 AC: 998 AN: 2102

Alfa AF: 0.413 Hom.: 10885

Bravo AF: 0.477

Asia WGS AF: 0.501 AC: 1741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.45
PhyloP100		-0.65
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: rs725693; hg19: chr14-79215810;