ENST00000520407.5:c.745+349547T>C

Variant names:

• chr8-31990276-T-C
• rs1462887
• ENST00000520407.5:c.745+349547T>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.745+349547T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 152,008 control chromosomes in the GnomAD database, including 41,505 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 0.73 (41505 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+350845T>C		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+350845T>C		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+350845T>C		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+349547T>C		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+349547T>C		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+350845T>C		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110805 AN: 151890 Hom.: 41475 Cov.: 33

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.741

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

GnomAD4 genome AF: 0.729 AC: 110885 AN: 152008 Hom.: 41505 Cov.: 33 AF XY: 0.727 AC XY: 54028 AN XY: 74286

African (AFR) AF: 0.588 AC: 24388 AN: 41470

American (AMR) AF: 0.754 AC: 11521 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2751 AN: 3470

East Asian (EAS) AF: 0.384 AC: 1966 AN: 5114

South Asian (SAS) AF: 0.783 AC: 3781 AN: 4830

European-Finnish (FIN) AF: 0.794 AC: 8416 AN: 10604

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55524 AN: 67934

Other (OTH) AF: 0.744 AC: 1569 AN: 2110

Alfa AF: 0.747 Hom.: 2447

Bravo AF: 0.716

Asia WGS AF: 0.640 AC: 2223 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.78
PhyloP100		1.5
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: rs1462887; hg19: chr8-31847792;