chr8-31640107-C-G

Variant names:

• chr8-31640107-C-G
• rs367543154
• ENST00000520407.5:c.123C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_013962.3(NRG1):​c.123C>G​(p.Thr41Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,150,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T41T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: NRG1 NM_013962.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• 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

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP7: Synonymous conserved (PhyloP=0.262 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013962.3. 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_013962.3		c.123C>G	p.Thr41Thr	synonymous	Exon 1 of 5	NP_039256.2	Q02297-9
	NRG1	NM_001159999.3		c.37+676C>G		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+676C>G		intron	N/A	NP_001153467.1	A0A494C1F8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.123C>G	p.Thr41Thr	synonymous	Exon 1 of 5	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000650866.1		c.37+676C>G		intron	N/A	ENSP00000499045.1	A0A494C1F5
	NRG1	ENST00000652698.1		c.37+676C>G		intron	N/A	ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148444 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 3 AN: 1001638 Hom.: 0 Cov.: 34 AF XY: 0.00000420 AC XY: 2 AN XY: 475634

African (AFR) AF: 0.00 AC: 0 AN: 19628

American (AMR) AF: 0.00 AC: 0 AN: 5732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10166

East Asian (EAS) AF: 0.00 AC: 0 AN: 18644

South Asian (SAS) AF: 0.0000497 AC: 1 AN: 20112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.00000230 AC: 2 AN: 870770

Other (OTH) AF: 0.00 AC: 0 AN: 37088

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148444 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72302

African (AFR) AF: 0.00 AC: 0 AN: 41062

American (AMR) AF: 0.00 AC: 0 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66610

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		0.26
PromoterAI		-0.0022	Neutral

Splicing

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

Other links and lift over

dbSNP: rs367543154; hg19: chr8-31497623;