8-31640457-C-T

Variant summary

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

The ENST00000520407.5(NRG1):c.473C>T(p.Ala158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,566,488 control chromosomes in the GnomAD database, including 164 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 0.018 (92 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: NRG1 ENST00000520407.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.87

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=0.0018194616).
• BP6: Variant 8-31640457-C-T is Benign according to our data. Variant chr8-31640457-C-T is described in ClinVar as [Benign]. Clinvar id is 3055726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013962.3	c.473C>T	p.Ala158Val	missense_variant	1/5
NRG1	XM_011544512.3	c.473C>T	p.Ala158Val	missense_variant	1/13
NRG1	XM_017013367.2	c.473C>T	p.Ala158Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000520407.5	c.473C>T	p.Ala158Val	missense_variant	1/5	1
NRG1	ENST00000523534.5	c.32C>T	p.Ala11Val	missense_variant	1/13	5
NRG1	ENST00000519301.6	c.37+1026C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2804 AN: 151916 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00636

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00352 AC: 646 AN: 183284 Hom.: 14 AF XY: 0.00272 AC XY: 278 AN XY: 102310

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00184 AC: 2601 AN: 1414458 Hom.: 72 Cov.: 34 AF XY: 0.00157 AC XY: 1100 AN XY: 700388

Gnomad4 AFR exome AF: 0.0672

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000271

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000514

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.0185 AC: 2810 AN: 152030 Hom.: 92 Cov.: 32 AF XY: 0.0178 AC XY: 1325 AN XY: 74324

Gnomad4 AFR AF: 0.0638

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.00465 Hom.: 11

Bravo AF: 0.0215

ESP6500AA AF: 0.0618 AC: 225

ESP6500EA AF: 0.000125 AC: 1

ExAC AF: 0.00497 AC: 592

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Pathogenic	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-0.15	N;.;N
REVEL	Benign	0.16
Sift	Uncertain	0.022	D;.;D
Sift4G	Pathogenic	0.0	D;D;T
Polyphen		0.63	P;.;.
Vest4		0.11
MVP		0.45
ClinPred		0.017	T
GERP RS		3.8

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61730349; hg19: chr8-31497973;