rs79223941

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-32760195-C-T
• chr8-32760195-C-A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 1285117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.1062-5C>T		splice_region intron	N/A	NP_039258.1	Q02297-1
	NRG1	NM_001322205.2		c.1242-5C>T		splice_region intron	N/A	NP_001309134.1	A0A494C0Q4
	NRG1	NM_013956.5		c.1077-5C>T		splice_region intron	N/A	NP_039250.2	Q02297-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.1062-5C>T		splice_region intron	N/A	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.1077-5C>T		splice_region intron	N/A	ENSP00000287842.4	Q02297-6
	NRG1	ENST00000356819.7	TSL:1	c.1053-5C>T		splice_region intron	N/A	ENSP00000349275.6	Q02297-7

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

GnomAD2 exomes AF: 0.0226 AC: 5669 AN: 250366 AF XY: 0.0238

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 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

African (AFR) AF: 0.00514 AC: 172 AN: 33472

American (AMR) AF: 0.0171 AC: 765 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00746 AC: 195 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.0175 AC: 1505 AN: 86222

European-Finnish (FIN) AF: 0.00962 AC: 513 AN: 53330

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5766

European-Non Finnish (NFE) AF: 0.0386 AC: 42902 AN: 1111738

Other (OTH) AF: 0.0291 AC: 1756 AN: 60378

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

African (AFR) AF: 0.00710 AC: 295 AN: 41536

American (AMR) AF: 0.0215 AC: 329 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4818

European-Finnish (FIN) AF: 0.00812 AC: 86 AN: 10590

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2372 AN: 68020

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0298 Hom.: 131

Bravo AF: 0.0224

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0380

EpiControl AF: 0.0383

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	NRG1-related disorder (1)
-	-	1	Schizophrenia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.40
PhyloP100		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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