ENST00000520407.5:c.746-53604C>A

Variant names:

• chr8-32542224-C-A
• rs10503919
• ENST00000520407.5:c.746-53604C>A

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-53604C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,104 control chromosomes in the GnomAD database, including 2,165 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 (2165 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-53604C>A		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-53604C>A		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-53604C>A		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.746-53604C>A		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-53604C>A		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-53604C>A		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23560 AN: 151986 Hom.: 2165 Cov.: 33

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.155 AC: 23553 AN: 152104 Hom.: 2165 Cov.: 33 AF XY: 0.157 AC XY: 11651 AN XY: 74336

African (AFR) AF: 0.0776 AC: 3221 AN: 41522

American (AMR) AF: 0.172 AC: 2629 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 797 AN: 3468

East Asian (EAS) AF: 0.0301 AC: 156 AN: 5180

South Asian (SAS) AF: 0.108 AC: 520 AN: 4816

European-Finnish (FIN) AF: 0.223 AC: 2348 AN: 10534

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13093 AN: 67984

Other (OTH) AF: 0.172 AC: 364 AN: 2114

Alfa AF: 0.179 Hom.: 9845

Bravo AF: 0.149

Asia WGS AF: 0.0660 AC: 228 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.36
PhyloP100		0.22
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: rs10503919; hg19: chr8-32399742;