rs10503929

Positions:

• chr8-32756465-T-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.866T>C​(p.Met289Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,406 control chromosomes in the GnomAD database, including 22,620 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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 0.12 (1577 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21043 hom.)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.80

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=0.0015502572).
• BP6: Variant 8-32756465-T-C is Benign according to our data. Variant chr8-32756465-T-C is described in ClinVar as [Benign]. Clinvar id is 3060016.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-32756465-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.866T>C	p.Met289Thr	missense_variant	9/12	ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.866T>C	p.Met289Thr	missense_variant	9/12	1	NM_013964.5	A2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18848 AN: 152054 Hom.: 1577 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.131 AC: 32899 AN: 250736 Hom.: 2843 AF XY: 0.132 AC XY: 17955 AN XY: 135526

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.0763

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0697

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.161 AC: 235965 AN: 1461234 Hom.: 21043 Cov.: 32 AF XY: 0.160 AC XY: 116229 AN XY: 726936

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.0804

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0704

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.124 AC: 18842 AN: 152172 Hom.: 1577 Cov.: 32 AF XY: 0.124 AC XY: 9232 AN XY: 74380

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0649

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.127

Alfa AF: 0.162 Hom.: 5400

Bravo AF: 0.111

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.167 AC: 644

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.181 AC: 1553

ExAC AF: 0.134 AC: 16282

Asia WGS AF: 0.0450 AC: 155 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	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.27	.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.097
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	.;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;.;.;.;.;L;.;L;.;.
MutationTaster	Benign	0.026	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.21	N;N;N;N;.;N;.;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.39	T;T;T;T;.;T;.;T;.;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;D
Polyphen		0.015, 0.0	.;.;.;.;B;B;B;B;.;.
Vest4		0.17, 0.37, 0.37, 0.38, 0.38, 0.43, 0.41
MPC		0.28
ClinPred		0.021	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10503929; hg19: chr8-32613983;