rs6468121

Variant names:

• chr8-32643290-G-T
• rs6468121
• NM_013964.5:c.502+26405G>T

Variant summary

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

The NM_013964.5(NRG1):​c.502+26405G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 151,936 control chromosomes in the GnomAD database, including 18,511 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 0.49 (18511 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+26405G>T		intron_variant	Intron 5 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.502+26405G>T		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74127 AN: 151818 Hom.: 18496 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.488 AC: 74186 AN: 151936 Hom.: 18511 Cov.: 32 AF XY: 0.486 AC XY: 36057 AN XY: 74248

African (AFR) AF: 0.517 AC: 21416 AN: 41408

American (AMR) AF: 0.477 AC: 7286 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3468

East Asian (EAS) AF: 0.125 AC: 648 AN: 5168

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4816

European-Finnish (FIN) AF: 0.551 AC: 5805 AN: 10530

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33771 AN: 67956

Other (OTH) AF: 0.498 AC: 1053 AN: 2116

Alfa AF: 0.500 Hom.: 3898

Bravo AF: 0.484

Asia WGS AF: 0.300 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.46
PhyloP100		-0.58
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: rs6468121; hg19: chr8-32500809;