chr8-31640175-C-A

Variant names:

• chr8-31640175-C-A
• rs367543155
• ENST00000520407.5:c.191C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013962.3(NRG1):​c.191C>A​(p.Ser64*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000964 in 1,037,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: NRG1 NM_013962.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• 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

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013962.3. 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_013962.3		c.191C>A	p.Ser64*	stop_gained	Exon 1 of 5	NP_039256.2	Q02297-9
	NRG1	NM_001159999.3		c.37+744C>A		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+744C>A		intron	N/A	NP_001153467.1	A0A494C1F8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.191C>A	p.Ser64*	stop_gained	Exon 1 of 5	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000650866.1		c.37+744C>A		intron	N/A	ENSP00000499045.1	A0A494C1F5
	NRG1	ENST00000652698.1		c.37+744C>A		intron	N/A	ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.64e-7 AC: 1 AN: 1037548 Hom.: 0 Cov.: 34 AF XY: 0.00000202 AC XY: 1 AN XY: 495684

African (AFR) AF: 0.00 AC: 0 AN: 20548

American (AMR) AF: 0.00 AC: 0 AN: 7150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11810

East Asian (EAS) AF: 0.00 AC: 0 AN: 21670

South Asian (SAS) AF: 0.0000420 AC: 1 AN: 23830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 891630

Other (OTH) AF: 0.00 AC: 0 AN: 39148

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.49	N
PhyloP100		2.4
Vest4		0.21
GERP RS		1.8
PromoterAI		0.019	Neutral
Mutation Taster		=47/153	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs367543155; hg19: chr8-31497691;