rs35641374

Variant names:

• chr8-32648114-G-C
• rs35641374
• ENST00000520502.7:c.397G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-32648114-G-C
• chr8-32648114-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001322205.2(NRG1):​c.397G>C​(p.Val133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,614,138 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (70 hom., cov: 32)
  • Exomes 𝑓: 0.018 (564 hom.)
• Consequence: NRG1 NM_001322205.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017232895).
• BP6: Variant 8-32648114-G-C is Benign according to our data. Variant chr8-32648114-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 218702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322205.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.502+31229G>C		intron	N/A	NP_039258.1	Q02297-1
	NRG1	NM_001322205.2		c.397G>C	p.Val133Leu	missense	Exon 1 of 9	NP_001309134.1	A0A494C0Q4
	NRG1	NM_001322206.2		c.397G>C	p.Val133Leu	missense	Exon 1 of 10	NP_001309135.1	A0A494C0L9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520502.7	TSL:1	c.397G>C	p.Val133Leu	missense	Exon 1 of 3	ENSP00000433289.1	Q02297-10
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.502+31229G>C		intron	N/A	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.502+31229G>C		intron	N/A	ENSP00000287842.4	Q02297-6

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 152134 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0502

GnomAD2 exomes AF: 0.0244 AC: 6142 AN: 251484 AF XY: 0.0267

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0358

GnomAD4 exome AF: 0.0184 AC: 26885 AN: 1461886 Hom.: 564 Cov.: 35 AF XY: 0.0201 AC XY: 14631 AN XY: 727244

African (AFR) AF: 0.0377 AC: 1262 AN: 33480

American (AMR) AF: 0.0254 AC: 1135 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0382 AC: 999 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0621 AC: 5360 AN: 86258

European-Finnish (FIN) AF: 0.00356 AC: 190 AN: 53414

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5768

European-Non Finnish (NFE) AF: 0.0141 AC: 15678 AN: 1112010

Other (OTH) AF: 0.0264 AC: 1593 AN: 60396

GnomAD4 genome AF: 0.0238 AC: 3630 AN: 152252 Hom.: 70 Cov.: 32 AF XY: 0.0243 AC XY: 1807 AN XY: 74438

African (AFR) AF: 0.0337 AC: 1400 AN: 41540

American (AMR) AF: 0.0282 AC: 431 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0605 AC: 291 AN: 4810

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10614

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1168 AN: 68022

Other (OTH) AF: 0.0497 AC: 105 AN: 2114

Alfa AF: 0.0199 Hom.: 44

Bravo AF: 0.0253

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0249 AC: 3022

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0264

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0070
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PROVEAN	Benign	0.26	N
REVEL	Benign	0.024
Sift	Benign	0.10	T
Sift4G	Benign	0.40	T
Polyphen		0.012	B
Vest4		0.050
MutPred		0.17		Gain of sheet (P = 0.0477)
ClinPred		0.0051	T
GERP RS		4.3
Mutation Taster		=89/11	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35641374; hg19: chr8-32505633; COSMIC: COSV55157546;