Genetic Variant NM_001330195.2:c.252C>T (chr14-78243345-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001330195.2(NRXN3):c.252C>T(p.Arg84Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,560,028 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 5 hom. )

Consequence

NRXN3
NM_001330195.2 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.13

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 14-78243345-C-T is Benign according to our data. Variant chr14-78243345-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3039208.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-4.14 with no splicing effect.

BS2

High AC in GnomAd4 at 103 AD gene.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NRXN3	NM_001330195.2	MANE Select	c.252C>T	p.Arg84Arg	synonymous	Exon 2 of 21	NP_001317124.1	A0A0A0MR89
NRXN3	NM_001366425.1		c.252C>T	p.Arg84Arg	synonymous	Exon 2 of 20	NP_001353354.1
NRXN3	NM_001366426.1		c.252C>T	p.Arg84Arg	synonymous	Exon 2 of 22	NP_001353355.1	A0A0U1RQC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.252C>T	p.Arg84Arg	synonymous	Exon 2 of 21	ENSP00000338349.7	A0A0A0MR89
NRXN3	ENST00000634499.2	TSL:5	c.252C>T	p.Arg84Arg	synonymous	Exon 2 of 22	ENSP00000488920.2	A0A0U1RQC5
NRXN3	ENST00000554738.5	TSL:5	c.252C>T	p.Arg84Arg	synonymous	Exon 1 of 20	ENSP00000450683.1	Q9Y4C0-4

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00115

AC:

197

AN:

170722

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.000546

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000766

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000836

AC:

1177

AN:

1407670

Hom.:

Cov.:

AF XY:

0.000990

AC XY:

690

AN XY:

696758

show subpopulations

African (AFR)

AF:

0.000644

AC:

AN:

32608

American (AMR)

AF:

0.000103

AC:

AN:

38922

Ashkenazi Jewish (ASJ)

AF:

0.000236

AC:

AN:

25426

East Asian (EAS)

AF:

0.0000532

AC:

AN:

37596

South Asian (SAS)

AF:

0.00549

AC:

444

AN:

80930

European-Finnish (FIN)

AF:

0.0000283

AC:

AN:

35340

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000593

AC:

648

AN:

1092226

Other (OTH)

AF:

0.000832

AC:

AN:

58898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152358

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

41594

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000384

Hom.:

Bravo

AF:

0.000631

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NRXN3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.60

(source)

DANN

Benign

0.78

PhyloP100

-4.1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over