19-18386449-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004864.4(GDF15):​c.260G>A​(p.Arg87Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GDF15
NM_004864.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.234
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.12704489).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GDF15NM_004864.4 linkc.260G>A p.Arg87Gln missense_variant Exon 1 of 2 ENST00000252809.3 NP_004855.2 Q99988

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GDF15ENST00000252809.3 linkc.260G>A p.Arg87Gln missense_variant Exon 1 of 2 1 NM_004864.4 ENSP00000252809.3 Q99988
GDF15ENST00000595973.3 linkc.260G>A p.Arg87Gln missense_variant Exon 2 of 3 5 ENSP00000470531.3 Q99988A0A0A0MTT8
GDF15ENST00000597765.2 linkc.260G>A p.Arg87Gln missense_variant Exon 2 of 3 4 ENSP00000469819.2 Q99988

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459886
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726008
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 07, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.260G>A (p.R87Q) alteration is located in exon 1 (coding exon 1) of the GDF15 gene. This alteration results from a G to A substitution at nucleotide position 260, causing the arginine (R) at amino acid position 87 to be replaced by a glutamine (Q). 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
0.087
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.54
T;T
M_CAP
Benign
0.079
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
1.1
.;L
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.22
.;N
REVEL
Benign
0.13
Sift
Uncertain
0.027
.;D
Sift4G
Benign
0.15
T;T
Polyphen
0.21
.;B
Vest4
0.062
MutPred
0.61
Loss of phosphorylation at T90 (P = 0.0718);Loss of phosphorylation at T90 (P = 0.0718);
MVP
0.64
MPC
0.77
ClinPred
0.12
T
GERP RS
0.019
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.040
gMVP
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1201798835; hg19: chr19-18497259; COSMIC: COSV105871025; COSMIC: COSV105871025; API