chr8-32548630-C-A

Variant names:

• chr8-32548630-C-A
• rs7834206
• NM_013964.5:c.-97C>A

Variant summary

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

The NM_013956.5(NRG1):​c.-97C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,443,660 control chromosomes in the GnomAD database, including 142,735 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 0.39 (12745 hom., cov: 34)
  • Exomes 𝑓: 0.44 (129990 hom.)
• Consequence: NRG1 NM_013956.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• Publications: 21 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.-97C>A		5_prime_UTR	Exon 1 of 12	NP_039258.1
	NRG1	NM_013956.5		c.-97C>A		5_prime_UTR	Exon 1 of 13	NP_039250.2
	NRG1	NM_013957.5		c.-97C>A		5_prime_UTR	Exon 1 of 12	NP_039251.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.-97C>A		5_prime_UTR	Exon 1 of 12	ENSP00000384620.2
	NRG1	ENST00000356819.7	TSL:1	c.-97C>A		5_prime_UTR	Exon 1 of 12	ENSP00000349275.6
	NRG1	ENST00000521670.5	TSL:1	c.-97C>A		5_prime_UTR	Exon 1 of 13	ENSP00000428828.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59514 AN: 151914 Hom.: 12738 Cov.: 34

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.352

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.443 AC: 572649 AN: 1291634 Hom.: 129990 Cov.: 36 AF XY: 0.443 AC XY: 279287 AN XY: 630242

African (AFR) AF: 0.217 AC: 5679 AN: 26212

American (AMR) AF: 0.526 AC: 11301 AN: 21476

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 7420 AN: 19782

East Asian (EAS) AF: 0.195 AC: 5927 AN: 30442

South Asian (SAS) AF: 0.416 AC: 26848 AN: 64468

European-Finnish (FIN) AF: 0.554 AC: 21271 AN: 38424

Middle Eastern (MID) AF: 0.329 AC: 1736 AN: 5274

European-Non Finnish (NFE) AF: 0.456 AC: 470519 AN: 1032206

Other (OTH) AF: 0.411 AC: 21948 AN: 53350

GnomAD4 genome AF: 0.392 AC: 59544 AN: 152026 Hom.: 12745 Cov.: 34 AF XY: 0.395 AC XY: 29338 AN XY: 74292

African (AFR) AF: 0.230 AC: 9539 AN: 41536

American (AMR) AF: 0.485 AC: 7419 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1342 AN: 3470

East Asian (EAS) AF: 0.175 AC: 893 AN: 5090

South Asian (SAS) AF: 0.408 AC: 1969 AN: 4822

European-Finnish (FIN) AF: 0.557 AC: 5896 AN: 10584

Middle Eastern (MID) AF: 0.358 AC: 103 AN: 288

European-Non Finnish (NFE) AF: 0.459 AC: 31157 AN: 67928

Other (OTH) AF: 0.387 AC: 817 AN: 2112

Alfa AF: 0.287 Hom.: 973

Bravo AF: 0.379

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.6
DANN	Benign	0.69
PhyloP100		0.35
PromoterAI		0.047	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs7834206; hg19: chr8-32406148; COSMIC: COSV55179946; COSMIC: COSV55179946;