8-31936593-A-G

Variant names:

• chr8-31936593-A-G
• rs1462872
• ENST00000520407.5:c.745+295864A>G

Variant summary

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

The ENST00000520407.5(NRG1):​c.745+295864A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 152,094 control chromosomes in the GnomAD database, including 44,006 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 (44006 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+297162A>G		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+297162A>G		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+297162A>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.745+295864A>G		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+295864A>G		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+297162A>G		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111252 AN: 151976 Hom.: 43981 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.851

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.771

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

GnomAD4 genome AF: 0.732 AC: 111308 AN: 152094 Hom.: 44006 Cov.: 32 AF XY: 0.731 AC XY: 54351 AN XY: 74346

African (AFR) AF: 0.431 AC: 17876 AN: 41438

American (AMR) AF: 0.807 AC: 12338 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 2956 AN: 3472

East Asian (EAS) AF: 0.386 AC: 1989 AN: 5154

South Asian (SAS) AF: 0.727 AC: 3508 AN: 4824

European-Finnish (FIN) AF: 0.874 AC: 9259 AN: 10590

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.893 AC: 60715 AN: 68004

Other (OTH) AF: 0.773 AC: 1635 AN: 2116

Alfa AF: 0.807 Hom.: 6456

Bravo AF: 0.711

Asia WGS AF: 0.595 AC: 2068 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.61
PhyloP100		0.56
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: rs1462872; hg19: chr8-31794109;