rs11626446

Variant names:

• chr14-78243701-G-A
• rs11626446
• NM_001330195.2:c.608G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-78243701-G-A
• chr14-78243701-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 8/11 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
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	NM_001330195.2	MANE Select	c.608G>A	p.Gly203Asp	missense	Exon 2 of 21	NP_001317124.1	A0A0A0MR89
	NRXN3	NM_001366425.1		c.608G>A	p.Gly203Asp	missense	Exon 2 of 20	NP_001353354.1
	NRXN3	NM_001366426.1		c.608G>A	p.Gly203Asp	missense	Exon 2 of 22	NP_001353355.1	A0A0U1RQC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN3	ENST00000335750.7	TSL:5 MANE Select	c.608G>A	p.Gly203Asp	missense	Exon 2 of 21	ENSP00000338349.7	A0A0A0MR89
	NRXN3	ENST00000634499.2	TSL:5	c.608G>A	p.Gly203Asp	missense	Exon 2 of 22	ENSP00000488920.2	A0A0U1RQC5
	NRXN3	ENST00000554738.5	TSL:5	c.608G>A	p.Gly203Asp	missense	Exon 1 of 20	ENSP00000450683.1	Q9Y4C0-4

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

GnomAD2 exomes AF: 0.236 AC: 54208 AN: 229268 AF XY: 0.245

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 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

African (AFR) AF: 0.106 AC: 3564 AN: 33474

American (AMR) AF: 0.125 AC: 5589 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7724 AN: 26134

East Asian (EAS) AF: 0.266 AC: 10543 AN: 39696

South Asian (SAS) AF: 0.235 AC: 20302 AN: 86258

European-Finnish (FIN) AF: 0.351 AC: 13360 AN: 38014

Middle Eastern (MID) AF: 0.314 AC: 1813 AN: 5766

European-Non Finnish (NFE) AF: 0.257 AC: 286064 AN: 1111686

Other (OTH) AF: 0.251 AC: 15129 AN: 60276

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

African (AFR) AF: 0.109 AC: 4515 AN: 41522

American (AMR) AF: 0.167 AC: 2549 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1251 AN: 5146

South Asian (SAS) AF: 0.237 AC: 1142 AN: 4810

European-Finnish (FIN) AF: 0.354 AC: 3744 AN: 10568

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18147 AN: 67966

Other (OTH) AF: 0.237 AC: 500 AN: 2112

Alfa AF: 0.244 Hom.: 16406

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
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
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
Sift4G	Benign	0.085	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

Other links and lift over

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