rs7005606

Variant names:

• chr8-32543983-T-G
• rs7005606
• ENST00000520407.5:c.746-51845T>G

Variant summary

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

The ENST00000520407.5(NRG1):​c.746-51845T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,110 control chromosomes in the GnomAD database, including 12,883 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 0.39 (12883 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 27 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-51845T>G		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.38-51845T>G		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.38-51845T>G		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.746-51845T>G		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-51845T>G		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-51845T>G		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60017 AN: 151992 Hom.: 12877 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.395 AC: 60045 AN: 152110 Hom.: 12883 Cov.: 32 AF XY: 0.398 AC XY: 29595 AN XY: 74336

African (AFR) AF: 0.230 AC: 9557 AN: 41498

American (AMR) AF: 0.488 AC: 7465 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1341 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1135 AN: 5166

South Asian (SAS) AF: 0.435 AC: 2100 AN: 4828

European-Finnish (FIN) AF: 0.557 AC: 5885 AN: 10560

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31211 AN: 67982

Other (OTH) AF: 0.393 AC: 831 AN: 2114

Alfa AF: 0.444 Hom.: 13072

Bravo AF: 0.382

Asia WGS AF: 0.387 AC: 1347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.71
PhyloP100		0.11
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: rs7005606; hg19: chr8-32401501;