rs3924999

Positions:

• chr8-32595840-G-A
• chr8-32595840-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_013964.5(NRG1):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,602,172 control chromosomes in the GnomAD database, including 132,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (9549 hom., cov: 32)
  • Exomes 𝑓: 0.40 (122776 hom.)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.37

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0896198E-6).
• BP6: Variant 8-32595840-G-A is Benign according to our data. Variant chr8-32595840-G-A is described in ClinVar as [Benign]. Clinvar id is 3059329.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-32595840-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_013964.5	c.113G>A	p.Arg38Gln	missense_variant	2/12	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.113G>A	p.Arg38Gln	missense_variant	2/12	1	NM_013964.5	ENSP00000384620	A2

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48749 AN: 151506 Hom.: 9560 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.399 AC: 98691 AN: 247262 Hom.: 22030 AF XY: 0.401 AC XY: 53645 AN XY: 133766

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.777

Gnomad SAS exome AF: 0.415

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.402 AC: 583779 AN: 1450548 Hom.: 122776 Cov.: 35 AF XY: 0.402 AC XY: 289904 AN XY: 721876

Gnomad4 AFR exome AF: 0.0996

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.401

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.321 AC: 48739 AN: 151624 Hom.: 9549 Cov.: 32 AF XY: 0.325 AC XY: 24041 AN XY: 74084

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.771

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.358

Alfa AF: 0.390 Hom.: 28904

Bravo AF: 0.319

TwinsUK AF: 0.406 AC: 1505

ALSPAC AF: 0.414 AC: 1595

ESP6500AA AF: 0.133 AC: 586

ESP6500EA AF: 0.396 AC: 3404

ExAC AF: 0.390 AC: 47361

Asia WGS AF: 0.547 AC: 1902 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NRG1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;T;.;.;.;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	.;T;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0000021	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	.;.;.;.;.;N;N;N;N;N
MutationTaster	Benign	0.86	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N;N;.;N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.044	D;D;D;D;.;D;D;T;D;D
Sift4G	Benign	0.074	T;T;T;T;T;D;D;D;D;D
Polyphen		0.70, 0.21, 0.047, 0.58	.;.;P;.;.;.;B;B;B;P
Vest4		0.069, 0.17, 0.23, 0.14, 0.17, 0.13, 0.15
MPC		0.28
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.081
gMVP		0.32

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3924999; hg19: chr8-32453358; COSMIC: COSV55177787;