Genetic Variant NRG1:p.Pro117Gln (chr8-31640334-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000520407.5(NRG1):c.350C>A(p.Pro117Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000967 in 1,034,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. 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. P117L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.7e-7 ( 0 hom. )

Consequence

NRG1
ENST00000520407.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.333

Publications

0 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:

ENSG00000302325 (HGNC:):

ENSG00000302325 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10363102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.350C>A	p.Pro117Gln	missense_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.350C>A	p.Pro117Gln	missense_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.350C>A	p.Pro117Gln	missense_variant	Exon 1 of 11	XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
NRG1	ENST00000520407.5 link	c.350C>A	p.Pro117Gln	missense_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+903C>A		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+903C>A		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.67e-7

AC:

AN:

1034500

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

488960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20982

American (AMR)

AF:

0.00

AC:

AN:

6820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11886

East Asian (EAS)

AF:

0.0000455

AC:

AN:

21996

South Asian (SAS)

AF:

0.00

AC:

AN:

19228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2648

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

891266

Other (OTH)

AF:

0.00

AC:

AN:

39890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.30

T;T

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.33

PROVEAN

Benign

-0.51

N;.

REVEL

Benign

0.11

Sift

Benign

0.49

T;.

Sift4G

Benign

0.27

T;T

Polyphen

0.0060

B;.

Vest4

0.24

MutPred

0.24

Loss of catalytic residue at P117 (P = 0.0152);Loss of catalytic residue at P117 (P = 0.0152);

MVP

0.45

ClinPred

0.031

GERP RS

-1.5

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr8-31640334-C-A

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