rs10503899

Variant names:

• chr8-32089718-A-G
• rs10503899
• ENST00000520407.5:c.745+448989A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000520407.5(NRG1):​c.745+448989A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,148 control chromosomes in the GnomAD database, including 10,378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (10378 hom., cov: 32)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.860
• Publications: 8 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-IT1 (HGNC:43633): (NRG1 intronic transcript 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.37+450287A>G		intron_variant	Intron 1 of 12		NP_001153471.1
NRG1	NM_001159995.3	c.37+450287A>G		intron_variant	Intron 1 of 11		NP_001153467.1
NRG1	NM_001160001.3	c.37+450287A>G		intron_variant	Intron 1 of 10		NP_001153473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.745+448989A>G		intron_variant	Intron 1 of 4	1		ENSP00000434640.1
NRG1-IT1	ENST00000521463.6	n.254-8963A>G		intron_variant	Intron 2 of 3	1
NRG1	ENST00000523534.5	c.304+448989A>G		intron_variant	Intron 1 of 12	5		ENSP00000429067.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50178 AN: 152028 Hom.: 10373 Cov.: 32

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.330 AC: 50190 AN: 152148 Hom.: 10378 Cov.: 32 AF XY: 0.330 AC XY: 24517 AN XY: 74368

African (AFR) AF: 0.0881 AC: 3663 AN: 41562

American (AMR) AF: 0.385 AC: 5891 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1448 AN: 3470

East Asian (EAS) AF: 0.126 AC: 656 AN: 5188

South Asian (SAS) AF: 0.413 AC: 1986 AN: 4814

European-Finnish (FIN) AF: 0.426 AC: 4487 AN: 10542

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30906 AN: 67972

Other (OTH) AF: 0.343 AC: 724 AN: 2112

Alfa AF: 0.418 Hom.: 23447

Bravo AF: 0.312

Asia WGS AF: 0.267 AC: 926 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.74
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10503899; hg19: chr8-31947234;