rs1054564

Positions:

• chr19-18389005-G-C

Variant summary

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

The NM_004864.4(GDF15):​c.*70G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,072,570 control chromosomes in the GnomAD database, including 10,156 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 0.11 (1111 hom., cov: 32)
  • Exomes 𝑓: 0.13 (9045 hom.)
• Consequence: GDF15 NM_004864.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF15	NM_004864.4	c.*70G>C		3_prime_UTR_variant	2/2	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000252809.3	c.*70G>C		3_prime_UTR_variant	2/2	1	NM_004864.4	ENSP00000252809.3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16702 AN: 152148 Hom.: 1112 Cov.: 32

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.135 AC: 124035 AN: 920304 Hom.: 9045 Cov.: 12 AF XY: 0.135 AC XY: 62680 AN XY: 464434

Gnomad4 AFR exome AF: 0.0416

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0766

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.110 AC: 16700 AN: 152266 Hom.: 1111 Cov.: 32 AF XY: 0.108 AC XY: 8069 AN XY: 74452

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.144

Alfa AF: 0.119 Hom.: 157

Bravo AF: 0.113

Asia WGS AF: 0.110 AC: 382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.79
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1054564; hg19: chr19-18499815;