rs34918173

chr8-32647818-C-Achr8-32647818-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000520502.7(NRG1):c.101C>A(p.Ala34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,613,906 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: NRG1 ENST00000520502.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020082295).
• BP6: Variant 8-32647818-C-A is Benign according to our data. Variant chr8-32647818-C-A is described in ClinVar as [Benign]. Clinvar id is 3038833.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1964/152064) while in subpopulation AFR AF= 0.0449 (1863/41476). AF 95% confidence interval is 0.0432. There are 40 homozygotes in gnomad4. There are 915 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1957 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.502+30933C>A		intron_variant		ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.502+30933C>A		intron_variant		1	NM_013964.5	A2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1957 AN: 151946 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00357 AC: 896 AN: 251214 Hom.: 23 AF XY: 0.00275 AC XY: 374 AN XY: 135810

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00136 AC: 1995 AN: 1461842 Hom.: 44 Cov.: 35 AF XY: 0.00121 AC XY: 877 AN XY: 727218

Gnomad4 AFR exome AF: 0.0472

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.0129 AC: 1964 AN: 152064 Hom.: 40 Cov.: 31 AF XY: 0.0123 AC XY: 915 AN XY: 74336

Gnomad4 AFR AF: 0.0449

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00247 Hom.: 14

Bravo AF: 0.0144

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00446 AC: 541

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Apr 16, 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	-0.57	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	-0.061
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.038
Sift	Benign	0.091	T
Sift4G	Benign	0.11	T
Polyphen		0.23	B
Vest4		0.33
MVP		0.34
ClinPred		0.0062	T
GERP RS		5.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34918173; hg19: chr8-32505337;