Variant rs1059519 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004864.4(GDF15):c.25G>A(p.Val9Met) 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 1,460,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V9L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06150055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF15	NM_004864.4 linkuse as main transcript	c.25G>A	p.Val9Met	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>A	p.Val9Met	missense_variant	1/2	1	NM_004864.4	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/3	5		ENSP00000470531.3	Q99988A0A0A0MTT8
GDF15	ENST00000597765.2 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/3	4		ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250524

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.2

DANN

Benign

0.90

DEOGEN2

Benign

0.040

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.020

.;N

REVEL

Benign

0.12

Sift

Benign

0.17

.;T

Sift4G

Benign

0.15

T;T

Polyphen

0.0010

.;B

Vest4

0.053

MutPred

0.19

Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.44

MPC

0.63

ClinPred

0.024

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

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