Genetic Variant NRXN3:c.3445-80583C>G (chr14-79583195-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001330195.2(NRXN3):c.3445-80583C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 152,022 control chromosomes in the GnomAD database, including 16,409 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 0.42 ( 16409 hom., cov: 32)

Consequence

NRXN3
NM_001330195.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.755

Publications

2 publications found

Variant links:

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

NRXN3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NRXN3	NM_001330195.2	MANE Select	c.3445-80583C>G	intron	N/A	NP_001317124.1
NRXN3	NM_001366425.1		c.3445-80583C>G	intron	N/A	NP_001353354.1
NRXN3	NM_001366426.1		c.3457-80583C>G	intron	N/A	NP_001353355.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.3445-80583C>G	intron	N/A	ENSP00000338349.7
NRXN3	ENST00000554719.5	TSL:1	c.2326-80583C>G	intron	N/A	ENSP00000451648.1
NRXN3	ENST00000428277.6	TSL:1	c.430-80583C>G	intron	N/A	ENSP00000394426.2

Frequencies

GnomAD3 genomes

AF:

0.419

AC:

63681

AN:

151904

Hom.:

16377

Cov.:

show subpopulations

Gnomad AFR

AF:

0.714

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.387

Gnomad EAS

AF:

0.562

Gnomad SAS

AF:

0.503

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.438

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

GnomAD4 genome

AF:

0.419

AC:

63760

AN:

152022

Hom.:

16409

Cov.:

AF XY:

0.418

AC XY:

31035

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.714

AC:

29609

AN:

41446

American (AMR)

AF:

0.308

AC:

4698

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1342

AN:

3468

East Asian (EAS)

AF:

0.562

AC:

2889

AN:

5142

South Asian (SAS)

AF:

0.504

AC:

2429

AN:

4816

European-Finnish (FIN)

AF:

0.243

AC:

2577

AN:

10586

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18923

AN:

67982

Other (OTH)

AF:

0.435

AC:

919

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1583

3165

4748

6330

7913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

564

1128

1692

2256

2820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.150

Hom.:

244

Bravo

AF:

0.436

Asia WGS

AF:

0.583

AC:

2027

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.73

(source)

DANN

Benign

0.62

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over