14-78476555-T-C

Variant names:

• chr14-78476555-T-C
• rs724373
• NM_001330195.2:c.758-168565T>C

Variant summary

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

The NM_001330195.2(NRXN3):​c.758-168565T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 152,188 control chromosomes in the GnomAD database, including 63,829 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 0.91 (63829 hom., cov: 31)
• Consequence: NRXN3 NM_001330195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN3	NM_001330195.2	c.758-168565T>C		intron_variant	Intron 4 of 20	ENST00000335750.7	NP_001317124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN3	ENST00000335750.7	c.758-168565T>C		intron_variant	Intron 4 of 20	5	NM_001330195.2	ENSP00000338349.7

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139014 AN: 152068 Hom.: 63787 Cov.: 31

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.953

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.912

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.931

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

GnomAD4 genome AF: 0.914 AC: 139112 AN: 152188 Hom.: 63829 Cov.: 31 AF XY: 0.914 AC XY: 68005 AN XY: 74392

African (AFR) AF: 0.865 AC: 35903 AN: 41510

American (AMR) AF: 0.953 AC: 14579 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3326 AN: 3470

East Asian (EAS) AF: 0.692 AC: 3580 AN: 5172

South Asian (SAS) AF: 0.957 AC: 4616 AN: 4824

European-Finnish (FIN) AF: 0.912 AC: 9670 AN: 10600

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.946 AC: 64315 AN: 68002

Other (OTH) AF: 0.931 AC: 1969 AN: 2114

Alfa AF: 0.941 Hom.: 29750

Bravo AF: 0.914

Asia WGS AF: 0.826 AC: 2868 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.59
DANN	Benign	0.77
PhyloP100		-0.75
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: rs724373; hg19: chr14-78942898;