ENST00000520407.5:c.746-253272C>A

Variant names:

• chr8-32342556-C-A
• rs1685103
• ENST00000520407.5:c.746-253272C>A

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-253272C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,162 control chromosomes in the GnomAD database, including 2,519 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 0.15 (2519 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.481
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520407.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_001159999.3		c.38-253272C>A		intron	N/A	NP_001153471.1
	NRG1	NM_001159995.3		c.38-253272C>A		intron	N/A	NP_001153467.1
	NRG1	NM_001160001.3		c.38-253272C>A		intron	N/A	NP_001153473.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.746-253272C>A		intron	N/A	ENSP00000434640.1
	NRG1	ENST00000523534.5	TSL:5	c.305-253272C>A		intron	N/A	ENSP00000429067.1
	NRG1	ENST00000650866.1		c.38-253272C>A		intron	N/A	ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22830 AN: 152044 Hom.: 2518 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.150 AC: 22867 AN: 152162 Hom.: 2519 Cov.: 33 AF XY: 0.154 AC XY: 11453 AN XY: 74408

African (AFR) AF: 0.224 AC: 9306 AN: 41508

American (AMR) AF: 0.142 AC: 2173 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3468

East Asian (EAS) AF: 0.581 AC: 2997 AN: 5154

South Asian (SAS) AF: 0.159 AC: 769 AN: 4828

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10592

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0820 AC: 5580 AN: 68014

Other (OTH) AF: 0.128 AC: 271 AN: 2110

Alfa AF: 0.102 Hom.: 544

Bravo AF: 0.159

Asia WGS AF: 0.301 AC: 1045 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.3
DANN	Benign	0.78
PhyloP100		0.48
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: rs1685103; hg19: chr8-32200072;