8-31640334-C-A

Variant names:

• chr8-31640334-C-A
• rs367543157
• ENST00000520407.5:c.350C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013962.3(NRG1):​c.350C>A​(p.Pro117Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000967 in 1,034,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P117L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: NRG1 NM_013962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10363102).

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.350C>A	p.Pro117Gln	missense	Exon 1 of 5	NP_039256.2	Q02297-9
	NRG1	NM_001159999.3		c.37+903C>A		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+903C>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.350C>A	p.Pro117Gln	missense	Exon 1 of 5	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000650866.1		c.37+903C>A		intron	N/A	ENSP00000499045.1	A0A494C1F5
	NRG1	ENST00000652698.1		c.37+903C>A		intron	N/A	ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.67e-7 AC: 1 AN: 1034500 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 488960

African (AFR) AF: 0.00 AC: 0 AN: 20982

American (AMR) AF: 0.00 AC: 0 AN: 6820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11886

East Asian (EAS) AF: 0.0000455 AC: 1 AN: 21996

South Asian (SAS) AF: 0.00 AC: 0 AN: 19228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 891266

Other (OTH) AF: 0.00 AC: 0 AN: 39890

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.94
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.33
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.11
Sift	Benign	0.49	T
Sift4G	Benign	0.27	T
Polyphen		0.0060	B
Vest4		0.24
MutPred		0.24		Loss of catalytic residue at P117 (P = 0.0152)
MVP		0.45
ClinPred		0.031	T
GERP RS		-1.5
PromoterAI		-0.013	Neutral
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: rs367543157; hg19: chr8-31497850;