Variant 19-18386214-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.157

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]

GDF15 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.25G>C	p.Val9Leu	missense_variant	1/2	ENST00000252809.3	NP_004855.2	Q99988

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GDF15	ENST00000252809.3 linkuse as main transcript	c.25G>C	p.Val9Leu	missense_variant	1/2	1	NM_004864.4	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3 linkuse as main transcript	c.25G>C	p.Val9Leu	missense_variant	2/3	5		ENSP00000470531.3	Q99988A0A0A0MTT8
GDF15	ENST00000597765.2 linkuse as main transcript	c.25G>C	p.Val9Leu	missense_variant	2/3	4		ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes

AF:

0.709

AC:

107788

AN:

152008

Hom.:

38476

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.667

AC XY:

484219

AN XY:

726154

show subpopulations

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.:

AF XY:

0.713

AC XY:

52999

AN XY:

74340

show subpopulations

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

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

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0000010

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

.;N

PrimateAI

Benign

0.31

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over