14-79854240-T-C

Variant names:

• chr14-79854240-T-C
• rs8019381
• NM_001330195.2:c.4094-7102T>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.4094-7102T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 693,374 control chromosomes in the GnomAD database, including 284,946 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 0.89 (60060 hom., cov: 31)
  • Exomes 𝑓: 0.91 (224886 hom.)
• Consequence: NRXN3 NM_001330195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 10 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

ENSG00000258416 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.4094-7102T>C		intron	N/A	NP_001317124.1
	NRXN3	NM_001366425.1		c.4004-7102T>C		intron	N/A	NP_001353354.1
	NRXN3	NM_001366426.1		c.4106-7423T>C		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.4094-7102T>C		intron	N/A	ENSP00000338349.7
	NRXN3	ENST00000554719.5	TSL:1	c.2885-7423T>C		intron	N/A	ENSP00000451648.1
	NRXN3	ENST00000428277.6	TSL:1	c.1079-7423T>C		intron	N/A	ENSP00000394426.2

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134976 AN: 151992 Hom.: 60023 Cov.: 31

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.919

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.866

GnomAD4 exome AF: 0.911 AC: 493184 AN: 541264 Hom.: 224886 Cov.: 7 AF XY: 0.911 AC XY: 231648 AN XY: 254396

African (AFR) AF: 0.830 AC: 8282 AN: 9982

American (AMR) AF: 0.930 AC: 571 AN: 614

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3003 AN: 3376

East Asian (EAS) AF: 0.999 AC: 2255 AN: 2258

South Asian (SAS) AF: 0.939 AC: 9922 AN: 10572

European-Finnish (FIN) AF: 0.925 AC: 544 AN: 588

Middle Eastern (MID) AF: 0.837 AC: 901 AN: 1076

European-Non Finnish (NFE) AF: 0.912 AC: 451735 AN: 495266

Other (OTH) AF: 0.911 AC: 15971 AN: 17532

GnomAD4 genome AF: 0.888 AC: 135066 AN: 152110 Hom.: 60060 Cov.: 31 AF XY: 0.890 AC XY: 66208 AN XY: 74372

African (AFR) AF: 0.837 AC: 34699 AN: 41470

American (AMR) AF: 0.891 AC: 13618 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.883 AC: 3065 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5169 AN: 5170

South Asian (SAS) AF: 0.942 AC: 4546 AN: 4824

European-Finnish (FIN) AF: 0.919 AC: 9711 AN: 10572

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61376 AN: 68010

Other (OTH) AF: 0.867 AC: 1831 AN: 2112

Alfa AF: 0.898 Hom.: 106280

Bravo AF: 0.882

Asia WGS AF: 0.962 AC: 3331 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0090
DANN	Benign	0.35
PhyloP100		0.24
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: rs8019381; hg19: chr14-80320583;