ENST00000520407.5:c.746-370908T>C

Variant names:

• chr8-32224920-T-C
• rs4733308
• ENST00000520407.5:c.746-370908T>C

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-370908T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 152,048 control chromosomes in the GnomAD database, including 20,404 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 0.49 (20404 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-370908T>C		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-370908T>C		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-370908T>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.746-370908T>C		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-370908T>C		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-370908T>C		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74492 AN: 151930 Hom.: 20396 Cov.: 33

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.511

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

GnomAD4 genome AF: 0.490 AC: 74522 AN: 152048 Hom.: 20404 Cov.: 33 AF XY: 0.496 AC XY: 36882 AN XY: 74342

African (AFR) AF: 0.236 AC: 9766 AN: 41468

American (AMR) AF: 0.645 AC: 9845 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1652 AN: 3468

East Asian (EAS) AF: 0.491 AC: 2544 AN: 5178

South Asian (SAS) AF: 0.608 AC: 2927 AN: 4812

European-Finnish (FIN) AF: 0.608 AC: 6430 AN: 10574

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39650 AN: 67964

Other (OTH) AF: 0.514 AC: 1084 AN: 2108

Alfa AF: 0.564 Hom.: 40084

Bravo AF: 0.482

Asia WGS AF: 0.568 AC: 1977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.4
DANN	Benign	0.53
PhyloP100		-0.024
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: rs4733308; hg19: chr8-32082436;