rs80127039

chr8-32764112-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013964.5(NRG1):c.1633C>T(p.Arg545Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,054 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R545Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (287 hom.)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 5.43

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=0.00954327).
• BP6: Variant 8-32764112-C-T is Benign according to our data. Variant chr8-32764112-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1285009.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-32764112-C-T is described in Lovd as [Likely_benign]. Variant chr8-32764112-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2081/152274) while in subpopulation NFE AF= 0.021 (1429/68028). AF 95% confidence interval is 0.0201. There are 19 homozygotes in gnomad4. There are 967 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2082 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.1633C>T	p.Arg545Trp	missense_variant	12/12	ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.1633C>T	p.Arg545Trp	missense_variant	12/12	1	NM_013964.5	A2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2082 AN: 152156 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0140 AC: 3513 AN: 250966 Hom.: 31 AF XY: 0.0141 AC XY: 1912 AN XY: 135640

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00845

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0188 AC: 27466 AN: 1461780 Hom.: 287 Cov.: 31 AF XY: 0.0184 AC XY: 13391 AN XY: 727196

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00944

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0137 AC: 2081 AN: 152274 Hom.: 19 Cov.: 32 AF XY: 0.0130 AC XY: 967 AN XY: 74460

Gnomad4 AFR AF: 0.00383

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0202

Gnomad4 NFE AF: 0.0210

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0190 Hom.: 50

Bravo AF: 0.0136

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0220 AC: 189

ExAC AF: 0.0141 AC: 1715

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0203

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
MetaRNN	Benign	0.0095	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;D;.;.;D
REVEL	Uncertain	0.44
Sift	Benign	0.097	T;T;.;.;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;.;D;D;D
Vest4		0.32
MPC		0.84
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.31
gMVP		0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80127039; hg19: chr8-32621630; COSMIC: COSV104382703; COSMIC: COSV104382703;