chr8-31976134-G-A

Variant names:

• chr8-31976134-G-A
• rs327417
• ENST00000520407.5:c.745+335405G>A

Variant summary

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

The ENST00000520407.5(NRG1):​c.745+335405G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 152,182 control chromosomes in the GnomAD database, including 55,455 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 0.85 (55455 hom., cov: 31)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644
• Publications: 2 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+336703G>A		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+336703G>A		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+336703G>A		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+335405G>A		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+335405G>A		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+336703G>A		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128754 AN: 152066 Hom.: 55386 Cov.: 31

Gnomad AFR AF: 0.962

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.838

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

GnomAD4 genome AF: 0.847 AC: 128883 AN: 152182 Hom.: 55455 Cov.: 31 AF XY: 0.841 AC XY: 62586 AN XY: 74388

African (AFR) AF: 0.962 AC: 39997 AN: 41558

American (AMR) AF: 0.817 AC: 12475 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2893 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1989 AN: 5138

South Asian (SAS) AF: 0.813 AC: 3923 AN: 4826

European-Finnish (FIN) AF: 0.797 AC: 8439 AN: 10594

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56396 AN: 68006

Other (OTH) AF: 0.839 AC: 1774 AN: 2114

Alfa AF: 0.849 Hom.: 8309

Bravo AF: 0.849

Asia WGS AF: 0.686 AC: 2386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.8
DANN	Benign	0.93
PhyloP100		0.64
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: rs327417; hg19: chr8-31833650;