Variant 14-78243275-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001330195.2(NRXN3):c.182C>T(p.Thr61Met) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,561,294 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 2 hom. )

Consequence

NRXN3
NM_001330195.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.99

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NRXN3. . Gene score misZ 3.438 (greater than the threshold 3.09). Trascript score misZ 4.1674 (greater than threshold 3.09). GenCC has associacion of gene with autism.

BP4

Computational evidence support a benign effect (MetaRNN=0.20626312).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN3	NM_001330195.2 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/21	ENST00000335750.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN3	ENST00000335750.7 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/21	5	NM_001330195.2	P1
NRXN3	ENST00000634499.2 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/22	5
NRXN3	ENST00000554738.5 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	1/20	5			Q9Y4C0-4

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000698

AC:

AN:

171866

Hom.:

AF XY:

0.0000532

AC XY:

AN XY:

94014

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000826

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000468

AC:

AN:

1408938

Hom.:

Cov.:

AF XY:

0.0000444

AC XY:

AN XY:

697454

show subpopulations

Gnomad4 AFR exome

AF:

0.000491

Gnomad4 AMR exome

AF:

0.000154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000990

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000220

Gnomad4 OTH exome

AF:

0.000136

GnomAD4 genome

AF:

0.000151

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000348

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NRXN3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The NRXN3 c.182C>T variant is predicted to result in the amino acid substitution p.Thr61Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.38

Sift4G

Uncertain

0.027

D;D

Vest4

0.23

GERP RS

5.9

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over