8-31640296-G-T

Variant names:

• chr8-31640296-G-T
• rs367543156
• ENST00000520407.5:c.312G>T

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.312G>T​(p.Ala104Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 984,592 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. A104A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: NRG1 NM_013962.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.322
• Publications: 0 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=-0.44).
• BP7: Synonymous conserved (PhyloP=0.322 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013962.3	c.312G>T	p.Ala104Ala	synonymous_variant	Exon 1 of 5		NP_039256.2
NRG1	XM_011544512.3	c.312G>T	p.Ala104Ala	synonymous_variant	Exon 1 of 13		XP_011542814.2
NRG1	XM_017013367.2	c.312G>T	p.Ala104Ala	synonymous_variant	Exon 1 of 11		XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.312G>T	p.Ala104Ala	synonymous_variant	Exon 1 of 5	1		ENSP00000434640.1
NRG1	ENST00000650866.1	c.37+865G>T		intron_variant	Intron 1 of 12			ENSP00000499045.1
NRG1	ENST00000652698.1	c.37+865G>T		intron_variant	Intron 1 of 11			ENSP00000499008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000711 AC: 7 AN: 984592 Hom.: 0 Cov.: 34 AF XY: 0.00000647 AC XY: 3 AN XY: 463962

African (AFR) AF: 0.00 AC: 0 AN: 19374

American (AMR) AF: 0.00 AC: 0 AN: 5374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9776

East Asian (EAS) AF: 0.00 AC: 0 AN: 17506

South Asian (SAS) AF: 0.00 AC: 0 AN: 18620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2390

European-Non Finnish (NFE) AF: 0.00000699 AC: 6 AN: 858586

Other (OTH) AF: 0.0000275 AC: 1 AN: 36308

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.32
PromoterAI		-0.035	Neutral

Splicing

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

Other links and lift over

dbSNP: rs367543156; hg19: chr8-31497812;