8-31640208-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000520407.5(NRG1):c.224T>C(p.Leu75Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,166,692 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (6 hom.)
• Consequence: NRG1 ENST00000520407.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.267

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014338702).
• BP6: Variant 8-31640208-T-C is Benign according to our data. Variant chr8-31640208-T-C is described in ClinVar as [Benign]. Clinvar id is 3056685.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000654 (97/148254) while in subpopulation EAS AF= 0.0187 (95/5074). AF 95% confidence interval is 0.0157. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013962.3	c.224T>C	p.Leu75Pro	missense_variant	1/5
NRG1	XM_011544512.3	c.224T>C	p.Leu75Pro	missense_variant	1/13
NRG1	XM_017013367.2	c.224T>C	p.Leu75Pro	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000520407.5	c.224T>C	p.Leu75Pro	missense_variant	1/5	1
NRG1	ENST00000519301.6	c.37+777T>C		intron_variant		5
NRG1	ENST00000650866.1	c.37+777T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000648 AC: 96 AN: 148146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.000289 AC: 294 AN: 1018438 Hom.: 6 Cov.: 34 AF XY: 0.000257 AC XY: 124 AN XY: 482340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0120

Gnomad4 SAS exome AF: 0.000335

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000797

Gnomad4 OTH exome AF: 0.000651

GnomAD4 genome AF: 0.000654 AC: 97 AN: 148254 Hom.: 0 Cov.: 32 AF XY: 0.000914 AC XY: 66 AN XY: 72228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000485

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00106

ExAC AF: 0.0000647 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.38	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.27	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.12	B;.
Vest4		0.55
MutPred		0.31		Gain of glycosylation at L75 (P = 0.0435);Gain of glycosylation at L75 (P = 0.0435);
MVP		0.57
ClinPred		0.50	D
GERP RS		1.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199941564; hg19: chr8-31497724; COSMIC: COSV73066237; COSMIC: COSV73066237;