19-18386214-G-C

Variant names:

• chr19-18386214-G-C
• rs1059519
• NM_004864.4:c.25G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004864.4(GDF15):​c.25G>C​(p.Val9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 1,611,978 control chromosomes in the GnomAD database, including 366,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (38514 hom., cov: 33)
  • Exomes 𝑓: 0.67 (327850 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• Publications: 49 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0130175E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF15	NM_004864.4	c.25G>C	p.Val9Leu	missense_variant	Exon 1 of 2	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000252809.3	c.25G>C	p.Val9Leu	missense_variant	Exon 1 of 2	1	NM_004864.4	ENSP00000252809.3
GDF15	ENST00000595973.3	c.25G>C	p.Val9Leu	missense_variant	Exon 2 of 3	5		ENSP00000470531.3
GDF15	ENST00000597765.2	c.25G>C	p.Val9Leu	missense_variant	Exon 2 of 3	4		ENSP00000469819.2
GDF15	ENST00000604609.2	n.*142G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107788 AN: 152008 Hom.: 38476 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.690 AC: 172826 AN: 250524 AF XY: 0.683

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.687

Gnomad EAS exome AF: 0.660

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.669 AC: 976833 AN: 1459852 Hom.: 327850 Cov.: 53 AF XY: 0.667 AC XY: 484219 AN XY: 726154

African (AFR) AF: 0.784 AC: 26183 AN: 33408

American (AMR) AF: 0.711 AC: 31768 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 18038 AN: 26126

East Asian (EAS) AF: 0.612 AC: 24304 AN: 39692

South Asian (SAS) AF: 0.636 AC: 54786 AN: 86178

European-Finnish (FIN) AF: 0.791 AC: 42180 AN: 53334

Middle Eastern (MID) AF: 0.608 AC: 2826 AN: 4648

European-Non Finnish (NFE) AF: 0.662 AC: 736297 AN: 1111522

Other (OTH) AF: 0.671 AC: 40451 AN: 60246

GnomAD4 genome AF: 0.709 AC: 107881 AN: 152126 Hom.: 38514 Cov.: 33 AF XY: 0.713 AC XY: 52999 AN XY: 74340

African (AFR) AF: 0.778 AC: 32298 AN: 41506

American (AMR) AF: 0.692 AC: 10582 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2456 AN: 3472

East Asian (EAS) AF: 0.659 AC: 3400 AN: 5156

South Asian (SAS) AF: 0.626 AC: 3015 AN: 4816

European-Finnish (FIN) AF: 0.810 AC: 8582 AN: 10598

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45356 AN: 67980

Other (OTH) AF: 0.661 AC: 1390 AN: 2102

Alfa AF: 0.663 Hom.: 8967

Bravo AF: 0.704

TwinsUK AF: 0.667 AC: 2474

ALSPAC AF: 0.665 AC: 2561

ESP6500AA AF: 0.787 AC: 3467

ESP6500EA AF: 0.659 AC: 5670

ExAC AF: 0.687 AC: 83399

Asia WGS AF: 0.661 AC: 2300 AN: 3478

EpiCase AF: 0.652

EpiControl AF: 0.653

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.4
DANN	Benign	0.43
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	.;N
PhyloP100		0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.42	.;N
REVEL	Benign	0.11
Sift	Benign	0.78	.;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	.;B
Vest4		0.019
MutPred		0.28		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MPC		0.62
ClinPred		0.00016	T
GERP RS		-1.7
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1059519; hg19: chr19-18497024; COSMIC: COSV53250533; COSMIC: COSV53250533;