Genetic Variant NRXN3:c.757+105271C>T (chr14-78403131-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.757+105271C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,054 control chromosomes in the GnomAD database, including 23,381 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 0.55 ( 23381 hom., cov: 32)

Consequence

NRXN3
NM_001330195.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0120

Publications

1 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=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 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.757+105271C>T	intron	N/A	NP_001317124.1
NRXN3	NM_001366425.1		c.757+105271C>T	intron	N/A	NP_001353354.1
NRXN3	NM_001366426.1		c.769+102440C>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.757+105271C>T	intron	N/A	ENSP00000338349.7
NRXN3	ENST00000634499.2	TSL:5	c.769+102440C>T	intron	N/A	ENSP00000488920.2
NRXN3	ENST00000554738.5	TSL:5	c.751+102440C>T	intron	N/A	ENSP00000450683.1

Frequencies

GnomAD3 genomes

AF:

0.551

AC:

83662

AN:

151934

Hom.:

23372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.570

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.612

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.545

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.586

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

GnomAD4 genome

AF:

0.551

AC:

83707

AN:

152054

Hom.:

23381

Cov.:

AF XY:

0.547

AC XY:

40676

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.621

AC:

25745

AN:

41484

American (AMR)

AF:

0.475

AC:

7259

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

2123

AN:

3468

East Asian (EAS)

AF:

0.620

AC:

3200

AN:

5158

South Asian (SAS)

AF:

0.543

AC:

2618

AN:

4820

European-Finnish (FIN)

AF:

0.477

AC:

5041

AN:

10572

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.527

AC:

35781

AN:

67958

Other (OTH)

AF:

0.584

AC:

1234

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1940

3880

5819

7759

9699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

728

1456

2184

2912

3640

<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:

0.539

Hom.:

11742

Bravo

AF:

0.558

Asia WGS

AF:

0.586

AC:

2039

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.1

(source)

DANN

Benign

0.71

PhyloP100

-0.012

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