Genetic Variant NRG1:p.Arg38Pro (chr8-32595840-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013964.5(NRG1):c.113G>C(p.Arg38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NRG1
NM_013964.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.37

Publications

115 publications found

Variant links:

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

NRG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5 link	c.113G>C	p.Arg38Pro	missense_variant	Exon 2 of 12	ENST00000405005.8	NP_039258.1	Q02297-1Q6PK61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8 link	c.113G>C	p.Arg38Pro	missense_variant	Exon 2 of 12	1	NM_013964.5	ENSP00000384620.2		Q02297-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1451694

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722432

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32722

American (AMR)

AF:

0.00

AC:

AN:

43390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25560

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85444

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107312

Other (OTH)

AF:

0.00

AC:

AN:

59652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.062893), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;.;T;.;.;.;.;.;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.51

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.49

.;.;.;.;.;N;N;N;N;N

PhyloP100

3.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

D;D;D;D;.;D;D;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;D;D;D;.;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99, 0.86, 0.77, 0.97

.;.;D;.;.;.;P;P;P;D

Vest4

0.48, 0.48, 0.52, 0.45, 0.43, 0.45, 0.46

MutPred

0.55

.;.;.;.;.;Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);

MVP

0.45

MPC

0.73

ClinPred

0.92

GERP RS

5.7

Varity_R

0.81

gMVP

0.77

Mutation Taster

=70/30

polymorphism

(source)

Splicing

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

Publications

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8-32595840-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over