Genetic Variant NRXN3:c.3263-34110C>T (chr14-79433111-C-T) – 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.3263-34110C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,000 control chromosomes in the GnomAD database, including 23,570 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 0.56 ( 23570 hom., cov: 33)

Consequence

NRXN3
NM_001330195.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.857

Publications

90 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=-0.93).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.617 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.3263-34110C>T	intron	N/A	NP_001317124.1
NRXN3	NM_001366425.1		c.3263-34110C>T	intron	N/A	NP_001353354.1
NRXN3	NM_001366426.1		c.3275-34110C>T	intron	N/A	NP_001353355.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.3263-34110C>T	intron	N/A	ENSP00000338349.7
NRXN3	ENST00000554719.5	TSL:1	c.2144-34110C>T	intron	N/A	ENSP00000451648.1
NRXN3	ENST00000428277.6	TSL:1	c.248-34110C>T	intron	N/A	ENSP00000394426.2

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84482

AN:

151880

Hom.:

23548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.589

Gnomad AMI

AF:

0.535

Gnomad AMR

AF:

0.627

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.435

Gnomad SAS

AF:

0.570

Gnomad FIN

AF:

0.591

Gnomad MID

AF:

0.510

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.569

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

GnomAD4 genome

AF:

0.556

AC:

84551

AN:

152000

Hom.:

23570

Cov.:

AF XY:

0.559

AC XY:

41535

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.589

AC:

24403

AN:

41444

American (AMR)

AF:

0.627

AC:

9572

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1699

AN:

3470

East Asian (EAS)

AF:

0.435

AC:

2252

AN:

5172

South Asian (SAS)

AF:

0.570

AC:

2747

AN:

4816

European-Finnish (FIN)

AF:

0.591

AC:

6228

AN:

10542

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.527

AC:

35816

AN:

67976

Other (OTH)

AF:

0.566

AC:

1196

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1946

3892

5839

7785

9731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<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:

0.536

Hom.:

77794

Bravo

AF:

0.561

Asia WGS

AF:

0.538

AC:

1871

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.24

(source)

DANN

Benign

0.53

PhyloP100

-0.86

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