Genetic Variant NRG1:p.Leu36Leu (chr8-31640092-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_013962.3(NRG1):c.108G>A(p.Leu36Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000723 in 1,134,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NRG1
NM_013962.3 synonymous

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 2.08

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP7

Synonymous conserved (PhyloP=2.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NRG1	NM_013962.3 link	c.108G>A	p.Leu36Leu	synonymous_variant	Exon 1 of 5	NP_039256.2	Q02297-9
NRG1	XM_011544512.3 link	c.108G>A	p.Leu36Leu	synonymous_variant	Exon 1 of 13	XP_011542814.2
NRG1	XM_017013367.2 link	c.108G>A	p.Leu36Leu	synonymous_variant	Exon 1 of 11	XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
NRG1	ENST00000520407.5 link	c.108G>A	p.Leu36Leu	synonymous_variant	Exon 1 of 5	1	ENSP00000434640.1	Q02297-9
NRG1	ENST00000650866.1 link	c.37+661G>A		intron_variant	Intron 1 of 12		ENSP00000499045.1	A0A494C1F5
NRG1	ENST00000652698.1 link	c.37+661G>A		intron_variant	Intron 1 of 11		ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes

AF:

0.000350

AC:

AN:

148444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

1236

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

986186

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

466172

show subpopulations

African (AFR)

AF:

0.000932

AC:

AN:

19322

American (AMR)

AF:

0.00

AC:

AN:

5320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9738

East Asian (EAS)

AF:

0.00

AC:

AN:

17316

South Asian (SAS)

AF:

0.000105

AC:

AN:

18962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2446

European-Non Finnish (NFE)

AF:

0.00000465

AC:

AN:

860526

Other (OTH)

AF:

0.0000826

AC:

AN:

36328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000370

AC:

AN:

148550

Hom.:

Cov.:

AF XY:

0.000442

AC XY:

AN XY:

72454

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

41148

American (AMR)

AF:

0.000200

AC:

AN:

14974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66634

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000351

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

Psychiatry Genetics Yale University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.1

PromoterAI

-0.011

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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chr8-31640092-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over