8-32548630-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013956.5(NRG1):​c.-97C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,292,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NRG1 NM_013956.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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>T		5_prime_UTR	Exon 1 of 12	NP_039258.1
	NRG1	NM_013956.5		c.-97C>T		5_prime_UTR	Exon 1 of 13	NP_039250.2
	NRG1	NM_013957.5		c.-97C>T		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>T		5_prime_UTR	Exon 1 of 12	ENSP00000384620.2
	NRG1	ENST00000356819.7	TSL:1	c.-97C>T		5_prime_UTR	Exon 1 of 12	ENSP00000349275.6
	NRG1	ENST00000521670.5	TSL:1	c.-97C>T		5_prime_UTR	Exon 1 of 13	ENSP00000428828.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1292398 Hom.: 0 Cov.: 36 AF XY: 0.00000159 AC XY: 1 AN XY: 630630

African (AFR) AF: 0.00 AC: 0 AN: 26228

American (AMR) AF: 0.00 AC: 0 AN: 21556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19810

East Asian (EAS) AF: 0.00 AC: 0 AN: 30460

South Asian (SAS) AF: 0.0000155 AC: 1 AN: 64532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032640

Other (OTH) AF: 0.0000187 AC: 1 AN: 53384

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.3
DANN	Benign	0.85
PhyloP100		0.35
PromoterAI		-0.0070	Neutral

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;