rs6574433

Variant names:

• chr14-78319816-A-G
• rs6574433
• NM_001330195.2:c.757+21956A>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.757+21956A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,166 control chromosomes in the GnomAD database, including 22,552 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 0.52 (22552 hom., cov: 33)
• Consequence: NRXN3 NM_001330195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• Publications: 15 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 (AFR) allele frequency at 95% confidence interval = 0.733 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	NM_001330195.2	MANE Select	c.757+21956A>G		intron	N/A	NP_001317124.1	A0A0A0MR89
	NRXN3	NM_001366425.1		c.757+21956A>G		intron	N/A	NP_001353354.1
	NRXN3	NM_001366426.1		c.769+19125A>G		intron	N/A	NP_001353355.1	A0A0U1RQC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.757+21956A>G		intron	N/A	ENSP00000338349.7	A0A0A0MR89
	NRXN3	ENST00000634499.2	TSL:5	c.769+19125A>G		intron	N/A	ENSP00000488920.2	A0A0U1RQC5
	NRXN3	ENST00000554738.5	TSL:5	c.751+19125A>G		intron	N/A	ENSP00000450683.1	Q9Y4C0-4

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79641 AN: 152048 Hom.: 22519 Cov.: 33

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.524 AC: 79714 AN: 152166 Hom.: 22552 Cov.: 33 AF XY: 0.520 AC XY: 38703 AN XY: 74384

African (AFR) AF: 0.740 AC: 30729 AN: 41532

American (AMR) AF: 0.364 AC: 5563 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3468

East Asian (EAS) AF: 0.680 AC: 3513 AN: 5164

South Asian (SAS) AF: 0.442 AC: 2133 AN: 4824

European-Finnish (FIN) AF: 0.446 AC: 4723 AN: 10586

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.439 AC: 29833 AN: 67996

Other (OTH) AF: 0.511 AC: 1080 AN: 2114

Alfa AF: 0.468 Hom.: 82586

Bravo AF: 0.530

Asia WGS AF: 0.532 AC: 1853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.96
DANN	Benign	0.71
PhyloP100		-0.51

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: rs6574433; hg19: chr14-78786159;