8-31895640-C-T

Variant names:

• chr8-31895640-C-T
• rs1383887
• ENST00000520407.5:c.745+254911C>T

Variant summary

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

The ENST00000520407.5(NRG1):​c.745+254911C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 151,814 control chromosomes in the GnomAD database, including 20,921 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 0.52 (20921 hom., cov: 31)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 1 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 (EAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+256209C>T		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+256209C>T		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+256209C>T		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+254911C>T		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.304+254911C>T		intron_variant	Intron 1 of 12	5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.37+256209C>T		intron_variant	Intron 1 of 12			ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78362 AN: 151696 Hom.: 20886 Cov.: 31

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.464

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

GnomAD4 genome AF: 0.517 AC: 78442 AN: 151814 Hom.: 20921 Cov.: 31 AF XY: 0.522 AC XY: 38714 AN XY: 74190

African (AFR) AF: 0.590 AC: 24400 AN: 41330

American (AMR) AF: 0.599 AC: 9147 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1604 AN: 3464

East Asian (EAS) AF: 0.748 AC: 3834 AN: 5126

South Asian (SAS) AF: 0.626 AC: 3016 AN: 4820

European-Finnish (FIN) AF: 0.432 AC: 4551 AN: 10538

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30240 AN: 67952

Other (OTH) AF: 0.466 AC: 985 AN: 2114

Alfa AF: 0.488 Hom.: 8700

Bravo AF: 0.533

Asia WGS AF: 0.658 AC: 2285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.97
DANN	Benign	0.71
PhyloP100		0.060
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1383887; hg19: chr8-31753156;