ENST00000595973.3:c.-274+580G>C

Variant names:

• chr19-18383027-G-C
• rs4808793
• ENST00000595973.3:c.-274+580G>C

Variant summary

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

The ENST00000595973.3(GDF15):​c.-274+580G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,110 control chromosomes in the GnomAD database, including 36,042 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 0.69 (36042 hom., cov: 32)
• Consequence: GDF15 ENST00000595973.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 19 publications found

Genes affected

GDF15 (HGNC:30142): (growth differentiation factor 15) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000595973.3	c.-274+580G>C		intron_variant	Intron 1 of 2	5		ENSP00000470531.3
GDF15	ENST00000597765.2	c.-273-2890G>C		intron_variant	Intron 1 of 2	4		ENSP00000469819.2
GDF15	ENST00000604609.2	n.350+580G>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104433 AN: 151992 Hom.: 36010 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.646

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

GnomAD4 genome AF: 0.687 AC: 104522 AN: 152110 Hom.: 36042 Cov.: 32 AF XY: 0.692 AC XY: 51450 AN XY: 74370

African (AFR) AF: 0.700 AC: 29050 AN: 41500

American (AMR) AF: 0.685 AC: 10454 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2454 AN: 3470

East Asian (EAS) AF: 0.659 AC: 3406 AN: 5172

South Asian (SAS) AF: 0.627 AC: 3031 AN: 4832

European-Finnish (FIN) AF: 0.810 AC: 8588 AN: 10608

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45383 AN: 67944

Other (OTH) AF: 0.642 AC: 1356 AN: 2112

Alfa AF: 0.628 Hom.: 2048

Bravo AF: 0.679

Asia WGS AF: 0.654 AC: 2277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.47
DANN	Benign	0.43
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Other links and lift over

dbSNP: rs4808793; hg19: chr19-18493837;