Genetic Variant NRXN3:c.1222-5732A>G (chr14-78703485-A-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.1222-5732A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 152,152 control chromosomes in the GnomAD database, including 25,231 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 0.53 ( 25231 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRXN3
NM_001330195.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.651

Publications

6 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:

ENSG00000258874 (HGNC:58461):

ENSG00000258874 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=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.671 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	UniProt
NRXN3	NM_001330195.2	MANE Select	c.1222-5732A>G	intron	N/A	NP_001317124.1	A0A0A0MR89
NRXN3	NM_001366425.1		c.1222-5732A>G	intron	N/A	NP_001353354.1
NRXN3	NM_001366426.1		c.1234-5732A>G	intron	N/A	NP_001353355.1	A0A0U1RQC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.1222-5732A>G	intron	N/A	ENSP00000338349.7	A0A0A0MR89
NRXN3	ENST00000554719.5	TSL:1	c.103-5732A>G	intron	N/A	ENSP00000451648.1	Q9Y4C0-3
NRXN3	ENST00000556496.2	TSL:1	n.566-5732A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.532

AC:

80891

AN:

152032

Hom.:

25219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.735

Gnomad AMR

AF:

0.625

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.569

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.746

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.676

Gnomad OTH

AF:

0.554

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.532

AC:

80916

AN:

152152

Hom.:

25231

Cov.:

AF XY:

0.537

AC XY:

39935

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.184

AC:

7645

AN:

41520

American (AMR)

AF:

0.625

AC:

9552

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2136

AN:

3472

East Asian (EAS)

AF:

0.569

AC:

2943

AN:

5174

South Asian (SAS)

AF:

0.573

AC:

2763

AN:

4820

European-Finnish (FIN)

AF:

0.746

AC:

7898

AN:

10586

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.676

AC:

45979

AN:

67980

Other (OTH)

AF:

0.553

AC:

1166

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1601

3201

4802

6402

8003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.627

Hom.:

58552

Bravo

AF:

0.508

Asia WGS

AF:

0.555

AC:

1929

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.5

(source)

DANN

Benign

0.64

PhyloP100

0.65

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