19-18388537-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004864.4(GDF15):c.529C>T(p.Arg177Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,444,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R177P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.237

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1923559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF15	NM_004864.4	c.529C>T	p.Arg177Trp	missense_variant	2/2	ENST00000252809.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF15	ENST00000252809.3	c.529C>T	p.Arg177Trp	missense_variant	2/2	1	NM_004864.4	P1
GDF15	ENST00000595973.3	c.529C>T	p.Arg177Trp	missense_variant	3/3	5		P1
GDF15	ENST00000597765.2	c.529C>T	p.Arg177Trp	missense_variant	3/3	4		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444718 Hom.: 0 Cov.: 35 AF XY: 0.00000278 AC XY: 2 AN XY: 718236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.529C>T (p.R177W) alteration is located in exon 2 (coding exon 2) of the GDF15 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the arginine (R) at amino acid position 177 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.055	T
Polyphen		0.46	P
Vest4		0.18
MutPred		0.24		Gain of sheet (P = 0.0344);
MVP		0.78
MPC		1.3
ClinPred		0.52	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18499347; COSMIC: COSV104580751; COSMIC: COSV104580751;