rs776401

Variant names:

• chr8-31859446-C-T
• rs776401
• ENST00000520407.5:c.745+218717C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000520407.5(NRG1):​c.745+218717C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,014 control chromosomes in the GnomAD database, including 37,828 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 0.70 (37828 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613
• Publications: 6 publications found

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

• schizophrenia 6

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+220015C>T		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+220015C>T		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+220015C>T		intron_variant	Intron 1 of 10		NP_001153473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.745+218717C>T		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+218717C>T		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+220015C>T		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106306 AN: 151898 Hom.: 37772 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.661

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

GnomAD4 genome AF: 0.700 AC: 106423 AN: 152014 Hom.: 37828 Cov.: 32 AF XY: 0.707 AC XY: 52552 AN XY: 74312

African (AFR) AF: 0.770 AC: 31915 AN: 41468

American (AMR) AF: 0.725 AC: 11075 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2014 AN: 3470

East Asian (EAS) AF: 0.921 AC: 4751 AN: 5156

South Asian (SAS) AF: 0.778 AC: 3753 AN: 4822

European-Finnish (FIN) AF: 0.707 AC: 7454 AN: 10540

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.636 AC: 43218 AN: 67972

Other (OTH) AF: 0.666 AC: 1402 AN: 2106

Alfa AF: 0.655 Hom.: 145041

Bravo AF: 0.703

Asia WGS AF: 0.852 AC: 2960 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.70
DANN	Benign	0.62
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776401; hg19: chr8-31716962;