rs10503929

Variant names:

• chr8-32756465-T-C
• rs10503929
• NM_013964.5:c.866T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 64 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3060016.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.866T>C	p.Met289Thr	missense_variant	Exon 9 of 12	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.866T>C	p.Met289Thr	missense_variant	Exon 9 of 12	1	NM_013964.5	ENSP00000384620.2

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

GnomAD2 exomes AF: 0.131 AC: 32899 AN: 250736 AF XY: 0.132

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 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

African (AFR) AF: 0.0249 AC: 834 AN: 33462

American (AMR) AF: 0.0804 AC: 3591 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3499 AN: 26122

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39684

South Asian (SAS) AF: 0.0704 AC: 6069 AN: 86208

European-Finnish (FIN) AF: 0.232 AC: 12354 AN: 53356

Middle Eastern (MID) AF: 0.127 AC: 731 AN: 5764

European-Non Finnish (NFE) AF: 0.180 AC: 200181 AN: 1111586

Other (OTH) AF: 0.144 AC: 8694 AN: 60362

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

African (AFR) AF: 0.0301 AC: 1250 AN: 41562

American (AMR) AF: 0.105 AC: 1604 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0649 AC: 312 AN: 4804

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10588

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12388 AN: 67978

Other (OTH) AF: 0.127 AC: 267 AN: 2108

Alfa AF: 0.156 Hom.: 7387

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

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.
PhyloP100		1.8
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
Mutation Taster		=86/14	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10503929; hg19: chr8-32613983; COSMIC: COSV107289349; COSMIC: COSV107289349;