chr19-18386214-G-C

Position:

• chr19-18386214-G-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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.

• 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

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=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/exons	MANE	Protein	UniProt
GDF15	NM_004864.4	c.25G>C	p.Val9Leu	missense_variant	1/2	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000252809.3	c.25G>C	p.Val9Leu	missense_variant	1/2	1	NM_004864.4	ENSP00000252809.3
GDF15	ENST00000595973.3	c.25G>C	p.Val9Leu	missense_variant	2/3	5		ENSP00000470531.3
GDF15	ENST00000597765.2	c.25G>C	p.Val9Leu	missense_variant	2/3	4		ENSP00000469819.2

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

GnomAD3 exomes AF: 0.690 AC: 172826 AN: 250524 Hom.: 59967 AF XY: 0.683 AC XY: 92609 AN XY: 135496

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 SAS exome AF: 0.637

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

Gnomad4 AFR exome AF: 0.784

Gnomad4 AMR exome AF: 0.711

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.612

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.791

Gnomad4 NFE exome AF: 0.662

Gnomad4 OTH exome AF: 0.671

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

Gnomad4 AFR AF: 0.778

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.659

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.661

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.28

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