NM_013964.5:c.414T>C

Variant names:

• chr8-32614527-T-C
• rs79277882
• NM_013964.5:c.414T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_013964.5(NRG1):​c.414T>C​(p.Gly138Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,674 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (11 hom.)
• Consequence: NRG1 NM_013964.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0900
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.218).
• BP6: Variant 8-32614527-T-C is Benign according to our data. Variant chr8-32614527-T-C is described in ClinVar as Benign. ClinVar VariationId is 780750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00694 (1056/152116) while in subpopulation AFR AF = 0.0237 (986/41538). AF 95% confidence interval is 0.0225. There are 13 homozygotes in GnomAd4. There are 480 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 12	NP_039258.1
	NRG1	NM_013956.5		c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 13	NP_039250.2
	NRG1	NM_013957.5		c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 12	NP_039251.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 12	ENSP00000384620.2
	NRG1	ENST00000287842.7	TSL:1	c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 13	ENSP00000287842.4
	NRG1	ENST00000356819.7	TSL:1	c.414T>C	p.Gly138Gly	synonymous	Exon 4 of 12	ENSP00000349275.6

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1047 AN: 152000 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

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: 0.0000736

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00180 AC: 451 AN: 250724 AF XY: 0.00131

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1460558 Hom.: 11 Cov.: 30 AF XY: 0.000586 AC XY: 426 AN XY: 726534

African (AFR) AF: 0.0228 AC: 763 AN: 33424

American (AMR) AF: 0.00172 AC: 77 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111062

Other (OTH) AF: 0.00167 AC: 101 AN: 60336

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152116 Hom.: 13 Cov.: 32 AF XY: 0.00645 AC XY: 480 AN XY: 74380

African (AFR) AF: 0.0237 AC: 986 AN: 41538

American (AMR) AF: 0.00348 AC: 53 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67938

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00239 Hom.: 9

Bravo AF: 0.00798

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.090
PromoterAI		0.024	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs79277882; hg19: chr8-32472045;