NM_013964.5:c.1062-5C>T

Variant names:

• chr8-32760195-C-T
• rs79223941
• NM_013964.5:c.1062-5C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013964.5(NRG1):​c.1062-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,613,620 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.033 (884 hom.)
• Consequence: NRG1 NM_013964.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001712
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.232

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-32760195-C-T is Benign according to our data. Variant chr8-32760195-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1285117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-32760195-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3273/152208) while in subpopulation NFE AF= 0.0349 (2372/68020). AF 95% confidence interval is 0.0337. There are 60 homozygotes in gnomad4. There are 1437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.1062-5C>T		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.1062-5C>T		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3276 AN: 152090 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00812

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0226 AC: 5669 AN: 250366 Hom.: 83 AF XY: 0.0238 AC XY: 3225 AN XY: 135386

Gnomad AFR exome AF: 0.00550

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.00718

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0328 AC: 47897 AN: 1461412 Hom.: 884 Cov.: 31 AF XY: 0.0323 AC XY: 23493 AN XY: 727000

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.00962

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0215 AC: 3273 AN: 152208 Hom.: 60 Cov.: 32 AF XY: 0.0193 AC XY: 1437 AN XY: 74416

Gnomad4 AFR AF: 0.00710

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00812

Gnomad4 NFE AF: 0.0349

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0235 Hom.: 24

Bravo AF: 0.0224

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0380

EpiControl AF: 0.0383

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Schizophrenia 6 Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 3.371% (rs79223941, 3,276/152,090 alleles, 48 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

NRG1-related disorder Benign:1

Oct 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs79223941; hg19: chr8-32617713; COSMIC: COSV104382608; COSMIC: COSV104382608;