rs4489283

Positions:

• chr8-32542144-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001159999.3(NRG1):​c.38-53684T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 151,960 control chromosomes in the GnomAD database, including 27,302 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 0.60 (27302 hom., cov: 32)
• Consequence: NRG1 NM_001159999.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_001159999.3	c.38-53684T>C		intron_variant			NP_001153471.1
NRG1	NM_001159995.3	c.38-53684T>C		intron_variant			NP_001153467.1
NRG1	NM_001160001.3	c.38-53684T>C		intron_variant			NP_001153473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.746-53684T>C		intron_variant		1		ENSP00000434640.1
NRG1	ENST00000523534.5	c.305-53684T>C		intron_variant		5		ENSP00000429067.1
NRG1	ENST00000650866.1	c.38-53684T>C		intron_variant				ENSP00000499045.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90637 AN: 151840 Hom.: 27281 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.610

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

GnomAD4 genome AF: 0.597 AC: 90687 AN: 151960 Hom.: 27302 Cov.: 32 AF XY: 0.597 AC XY: 44310 AN XY: 74264

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.572

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.744

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.588

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.602

Alfa AF: 0.604 Hom.: 55947

Bravo AF: 0.595

Asia WGS AF: 0.608 AC: 2113 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.19
DANN	Benign	0.33

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4489283; hg19: chr8-32399662;