rs372373

Variant names:

• chr8-31990023-T-C
• rs372373
• ENST00000520407.5:c.745+349294T>C

Variant summary

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

The NM_001159999.3(NRG1):​c.37+350592T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 152,126 control chromosomes in the GnomAD database, including 53,881 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 0.84 (53881 hom., cov: 33)
• Consequence: NRG1 NM_001159999.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_001159999.3		c.37+350592T>C		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+350592T>C		intron	N/A	NP_001153467.1	A0A494C1F8
	NRG1	NM_001160001.3		c.37+350592T>C		intron	N/A	NP_001153473.1	Q02297-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.745+349294T>C		intron	N/A	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000523534.5	TSL:5	c.304+349294T>C		intron	N/A	ENSP00000429067.1	H0YBA3
	NRG1	ENST00000650866.1		c.37+350592T>C		intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes AF: 0.836 AC: 127052 AN: 152008 Hom.: 53815 Cov.: 33

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.829

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

GnomAD4 genome AF: 0.836 AC: 127178 AN: 152126 Hom.: 53881 Cov.: 33 AF XY: 0.831 AC XY: 61803 AN XY: 74358

African (AFR) AF: 0.925 AC: 38433 AN: 41544

American (AMR) AF: 0.813 AC: 12412 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2889 AN: 3468

East Asian (EAS) AF: 0.386 AC: 1983 AN: 5132

South Asian (SAS) AF: 0.813 AC: 3925 AN: 4828

European-Finnish (FIN) AF: 0.795 AC: 8432 AN: 10600

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56352 AN: 67970

Other (OTH) AF: 0.830 AC: 1755 AN: 2114

Alfa AF: 0.841 Hom.: 11213

Bravo AF: 0.836

Asia WGS AF: 0.681 AC: 2368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.38
PhyloP100		-0.060
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: rs372373; hg19: chr8-31847539;