8-31672512-T-G

Variant names:

• chr8-31672512-T-G
• rs4560751
• ENST00000520407.5:c.745+31783T>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+31783T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 152,020 control chromosomes in the GnomAD database, including 47,594 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 0.78 (47594 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+33081T>G		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+33081T>G		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+33081T>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+31783T>G		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+31783T>G		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+33081T>G		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.783 AC: 118900 AN: 151902 Hom.: 47558 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.947

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.834

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

GnomAD4 genome AF: 0.783 AC: 118986 AN: 152020 Hom.: 47594 Cov.: 32 AF XY: 0.783 AC XY: 58207 AN XY: 74296

African (AFR) AF: 0.604 AC: 25019 AN: 41454

American (AMR) AF: 0.760 AC: 11601 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3117 AN: 3470

East Asian (EAS) AF: 0.989 AC: 5112 AN: 5168

South Asian (SAS) AF: 0.876 AC: 4215 AN: 4814

European-Finnish (FIN) AF: 0.810 AC: 8559 AN: 10572

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58469 AN: 67964

Other (OTH) AF: 0.836 AC: 1767 AN: 2114

Alfa AF: 0.714 Hom.: 3387

Bravo AF: 0.770

Asia WGS AF: 0.893 AC: 3105 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-0.15
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: rs4560751; hg19: chr8-31530028;