chr8-31640156-G-A

Variant names:

• chr8-31640156-G-A
• rs113317778
• ENST00000520407.5:c.172G>A

Variant summary

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

The NM_013962.3(NRG1):​c.172G>A​(p.Gly58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,176,150 control chromosomes in the GnomAD database, including 9,403 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1427 hom., cov: 32)
  • Exomes 𝑓: 0.12 (7976 hom.)
• Consequence: NRG1 NM_013962.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20
• Publications: 14 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

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021058023).
• BP6: Variant 8-31640156-G-A is Benign according to our data. Variant chr8-31640156-G-A is described in ClinVar as [Benign]. Clinvar id is 1328708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013962.3	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 5		NP_039256.2
NRG1	XM_011544512.3	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 13		XP_011542814.2
NRG1	XM_017013367.2	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 11		XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.172G>A	p.Gly58Arg	missense_variant	Exon 1 of 5	1		ENSP00000434640.1
NRG1	ENST00000650866.1	c.37+725G>A		intron_variant	Intron 1 of 12			ENSP00000499045.1
NRG1	ENST00000652698.1	c.37+725G>A		intron_variant	Intron 1 of 11			ENSP00000499008.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19567 AN: 148312 Hom.: 1425 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00448

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0865

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.141 AC: 827 AN: 5858 AF XY: 0.142

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.121 AC: 124639 AN: 1027736 Hom.: 7976 Cov.: 35 AF XY: 0.121 AC XY: 59254 AN XY: 489586

African (AFR) AF: 0.142 AC: 2900 AN: 20368

American (AMR) AF: 0.258 AC: 1807 AN: 6992

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 808 AN: 11466

East Asian (EAS) AF: 0.0103 AC: 217 AN: 21106

South Asian (SAS) AF: 0.142 AC: 3163 AN: 22216

European-Finnish (FIN) AF: 0.138 AC: 2554 AN: 18504

Middle Eastern (MID) AF: 0.0966 AC: 258 AN: 2670

European-Non Finnish (NFE) AF: 0.123 AC: 108638 AN: 885794

Other (OTH) AF: 0.111 AC: 4294 AN: 38620

GnomAD4 genome AF: 0.132 AC: 19578 AN: 148414 Hom.: 1427 Cov.: 32 AF XY: 0.134 AC XY: 9659 AN XY: 72322

African (AFR) AF: 0.147 AC: 6067 AN: 41216

American (AMR) AF: 0.193 AC: 2889 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 276 AN: 3396

East Asian (EAS) AF: 0.00450 AC: 23 AN: 5114

South Asian (SAS) AF: 0.139 AC: 671 AN: 4816

European-Finnish (FIN) AF: 0.139 AC: 1280 AN: 9204

Middle Eastern (MID) AF: 0.0862 AC: 25 AN: 290

European-Non Finnish (NFE) AF: 0.122 AC: 8106 AN: 66444

Other (OTH) AF: 0.104 AC: 215 AN: 2062

Alfa AF: 0.125 Hom.: 379

ESP6500AA AF: 0.105 AC: 150

ESP6500EA AF: 0.0916 AC: 305

ExAC AF: 0.0760 AC: 931

Asia WGS AF: 0.0760 AC: 223 AN: 2930

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-0.50	N;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.30		Gain of methylation at G58 (P = 0.0148);Gain of methylation at G58 (P = 0.0148);
ClinPred		0.082	T
GERP RS		1.4
PromoterAI		0.055	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs113317778; hg19: chr8-31497672;