rs1059369

chr19-18386331-T-Achr19-18386331-T-Cchr19-18386331-T-G

Variant summary

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

The NM_004864.4(GDF15):c.142T>A(p.Ser48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,728 control chromosomes in the GnomAD database, including 48,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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.

• Frequency:
  • Genomes: 𝑓 0.24 (4733 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43849 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215

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=0.0019753575).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF15	NM_004864.4	c.142T>A	p.Ser48Thr	missense_variant	1/2	ENST00000252809.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF15	ENST00000252809.3	c.142T>A	p.Ser48Thr	missense_variant	1/2	1	NM_004864.4	P1
GDF15	ENST00000595973.3	c.142T>A	p.Ser48Thr	missense_variant	2/3	5		P1
GDF15	ENST00000597765.2	c.142T>A	p.Ser48Thr	missense_variant	2/3	4		P1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36599 AN: 151936 Hom.: 4727 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.273 AC: 68427 AN: 250812 Hom.: 10237 AF XY: 0.265 AC XY: 35959 AN XY: 135656

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.389

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.240 AC: 350953 AN: 1461674 Hom.: 43849 Cov.: 37 AF XY: 0.238 AC XY: 173029 AN XY: 727146

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.231

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.241 AC: 36639 AN: 152054 Hom.: 4733 Cov.: 32 AF XY: 0.246 AC XY: 18285 AN XY: 74306

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.223

Alfa AF: 0.221 Hom.: 3009

Bravo AF: 0.242

TwinsUK AF: 0.225 AC: 835

ALSPAC AF: 0.234 AC: 902

ESP6500AA AF: 0.182 AC: 803

ESP6500EA AF: 0.238 AC: 2049

ExAC AF: 0.263 AC: 31984

Asia WGS AF: 0.282 AC: 980 AN: 3478

EpiCase AF: 0.219

EpiControl AF: 0.228

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.7
Dann	Benign	0.96
DEOGEN2	Benign	0.093	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.35	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.046	D;T
Polyphen		0.68	.;P
Vest4		0.062
MPC		0.81
ClinPred		0.0035	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.23

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: rs1059369; hg19: chr19-18497141; COSMIC: COSV53250556; COSMIC: COSV53250556;