rs1058587

chr19-18388612-C-Gchr19-18388612-C-T

Variant summary

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

The NM_004864.4(GDF15):c.604C>G(p.His202Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,598,956 control chromosomes in the GnomAD database, including 50,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H202R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3873 hom., cov: 34)
  • Exomes 𝑓: 0.25 (46642 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.634

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 (MetaRNN=0.0035499632).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF15	NM_004864.4	c.604C>G	p.His202Asp	missense_variant	2/2	ENST00000252809.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF15	ENST00000252809.3	c.604C>G	p.His202Asp	missense_variant	2/2	1	NM_004864.4	P1
GDF15	ENST00000595973.3	c.604C>G	p.His202Asp	missense_variant	3/3	5		P1
GDF15	ENST00000597765.2	c.604C>G	p.His202Asp	missense_variant	3/3	4		P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33545 AN: 152154 Hom.: 3875 Cov.: 34

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.220

GnomAD3 exomes AF: 0.243 AC: 53675 AN: 220972 Hom.: 6693 AF XY: 0.250 AC XY: 30773 AN XY: 123056

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.259

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.251 AC: 362783 AN: 1446684 Hom.: 46642 Cov.: 38 AF XY: 0.253 AC XY: 181921 AN XY: 719490

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.220 AC: 33545 AN: 152272 Hom.: 3873 Cov.: 34 AF XY: 0.220 AC XY: 16395 AN XY: 74462

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.219

Alfa AF: 0.206 Hom.: 1049

Bravo AF: 0.209

TwinsUK AF: 0.261 AC: 969

ALSPAC AF: 0.254 AC: 980

ESP6500AA AF: 0.143 AC: 607

ESP6500EA AF: 0.221 AC: 1845

ExAC AF: 0.237 AC: 28149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	4.8
Dann	Benign	0.75
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.037
Sift	Benign	0.49	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.86
ClinPred		0.00030	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.61

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: rs1058587; hg19: chr19-18499422; COSMIC: COSV53250733; COSMIC: COSV53250733;