14-78243701-G-A

Position:

• chr14-78243701-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001330195.2(NRXN3):​c.608G>A​(p.Gly203Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,598,102 control chromosomes in the GnomAD database, including 51,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4102 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47257 hom.)
• Consequence: NRXN3 NM_001330195.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Benign. Variant got -19 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=0.003507167).
• BP6: Variant 14-78243701-G-A is Benign according to our data. Variant chr14-78243701-G-A is described in ClinVar as [Benign]. Clinvar id is 674091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN3	NM_001330195.2	c.608G>A	p.Gly203Asp	missense_variant	2/21	ENST00000335750.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN3	ENST00000335750.7	c.608G>A	p.Gly203Asp	missense_variant	2/21	5	NM_001330195.2	P1
NRXN3	ENST00000634499.2	c.608G>A	p.Gly203Asp	missense_variant	2/22	5
NRXN3	ENST00000554738.5	c.608G>A	p.Gly203Asp	missense_variant	1/20	5
NRXN3	ENST00000556088.1	n.100G>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33156 AN: 151964 Hom.: 4097 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.236 AC: 54208 AN: 229268 Hom.: 7036 AF XY: 0.245 AC XY: 31032 AN XY: 126720

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.356

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.252 AC: 364088 AN: 1446020 Hom.: 47257 Cov.: 37 AF XY: 0.253 AC XY: 182307 AN XY: 719722

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.218 AC: 33169 AN: 152082 Hom.: 4102 Cov.: 32 AF XY: 0.223 AC XY: 16548 AN XY: 74328

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.237

Alfa AF: 0.254 Hom.: 10624

Bravo AF: 0.199

TwinsUK AF: 0.259 AC: 960

ALSPAC AF: 0.239 AC: 921

ESP6500AA AF: 0.112 AC: 197

ESP6500EA AF: 0.270 AC: 1075

ExAC AF: 0.243 AC: 27856

Asia WGS AF: 0.230 AC: 801 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.0	T
Sift4G	Benign	0.085	T;T
Vest4		0.045
GERP RS		3.1
gMVP		0.68

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

Other links and lift over

dbSNP: rs11626446; hg19: chr14-78710044; COSMIC: COSV73587254;