rs79916768

Variant names:

• chr8-32743286-A-G
• rs79916768
• NM_013964.5:c.700+1211A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_013964.5(NRG1):​c.700+1211A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 918,786 control chromosomes in the GnomAD database, including 365 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 0.023 (68 hom., cov: 32)
  • Exomes 𝑓: 0.026 (297 hom.)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• 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=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3492/152206) while in subpopulation NFE AF = 0.0299 (2032/67996). AF 95% confidence interval is 0.0288. There are 68 homozygotes in GnomAd4. There are 1817 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. 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_013964.5	MANE Select	c.700+1211A>G		intron	N/A	NP_039258.1	Q02297-1
	NRG1	NM_001322205.2		c.856+553A>G		intron	N/A	NP_001309134.1	A0A494C0Q4
	NRG1	NM_013956.5		c.691+553A>G		intron	N/A	NP_039250.2	Q02297-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.700+1211A>G		intron	N/A	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.691+553A>G		intron	N/A	ENSP00000287842.4	Q02297-6
	NRG1	ENST00000356819.7	TSL:1	c.691+553A>G		intron	N/A	ENSP00000349275.6	Q02297-7

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3492 AN: 152090 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0229

GnomAD4 exome AF: 0.0259 AC: 19841 AN: 766580 Hom.: 297 Cov.: 11 AF XY: 0.0258 AC XY: 9161 AN XY: 355540

African (AFR) AF: 0.00299 AC: 43 AN: 14398

American (AMR) AF: 0.0136 AC: 12 AN: 880

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 124 AN: 4738

East Asian (EAS) AF: 0.000307 AC: 1 AN: 3258

South Asian (SAS) AF: 0.00883 AC: 133 AN: 15064

European-Finnish (FIN) AF: 0.0504 AC: 13 AN: 258

Middle Eastern (MID) AF: 0.0135 AC: 20 AN: 1482

European-Non Finnish (NFE) AF: 0.0270 AC: 18935 AN: 701534

Other (OTH) AF: 0.0224 AC: 560 AN: 24968

GnomAD4 genome AF: 0.0229 AC: 3492 AN: 152206 Hom.: 68 Cov.: 32 AF XY: 0.0244 AC XY: 1817 AN XY: 74396

African (AFR) AF: 0.00471 AC: 196 AN: 41570

American (AMR) AF: 0.0206 AC: 314 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.0740 AC: 783 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2032 AN: 67996

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0261 Hom.: 19

Bravo AF: 0.0179

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.50
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs79916768; hg19: chr8-32600804;