8-31640156-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000520407.5(NRG1):c.172G>A(p.Gly58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,176,150 control chromosomes in the GnomAD database, including 9,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1427 hom., cov: 32)
  • Exomes 𝑓: 0.12 (7976 hom.)
• Consequence: NRG1 ENST00000520407.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021058023).
• BP6: Variant 8-31640156-G-A is Benign according to our data. Variant chr8-31640156-G-A is described in ClinVar as [Benign]. Clinvar id is 1328708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013962.3	c.172G>A	p.Gly58Arg	missense_variant	1/5
NRG1	XM_011544512.3	c.172G>A	p.Gly58Arg	missense_variant	1/13
NRG1	XM_017013367.2	c.172G>A	p.Gly58Arg	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000520407.5	c.172G>A	p.Gly58Arg	missense_variant	1/5	1
NRG1	ENST00000519301.6	c.37+725G>A		intron_variant		5
NRG1	ENST00000650866.1	c.37+725G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19567 AN: 148312 Hom.: 1425 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00448

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0865

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.141 AC: 827 AN: 5858 Hom.: 89 AF XY: 0.142 AC XY: 519 AN XY: 3650

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.121 AC: 124639 AN: 1027736 Hom.: 7976 Cov.: 35 AF XY: 0.121 AC XY: 59254 AN XY: 489586

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.132 AC: 19578 AN: 148414 Hom.: 1427 Cov.: 32 AF XY: 0.134 AC XY: 9659 AN XY: 72322

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.0813

Gnomad4 EAS AF: 0.00450

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.104

Alfa AF: 0.136 Hom.: 192

ESP6500AA AF: 0.105 AC: 150

ESP6500EA AF: 0.0916 AC: 305

ExAC AF: 0.0760 AC: 931

Asia WGS AF: 0.0760 AC: 223 AN: 2930

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-0.50	N;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.30		Gain of methylation at G58 (P = 0.0148);Gain of methylation at G58 (P = 0.0148);
ClinPred		0.082	T
GERP RS		1.4

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113317778; hg19: chr8-31497672;