Variant rs1058587 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.604C>G(p.His202Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,598,956 control chromosomes in the GnomAD database, including 50,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.22 ( 3873 hom., cov: 34)

Exomes 𝑓: 0.25 ( 46642 hom. )

Consequence

GDF15
NM_004864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.634

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=0.0035499632).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.296 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.604C>G	p.His202Asp	missense_variant	2/2	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.604C>G	p.His202Asp	missense_variant	2/2	1	NM_004864.4	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3 linkuse as main transcript	c.604C>G	p.His202Asp	missense_variant	3/3	5		ENSP00000470531.3	Q99988A0A0A0MTT8
GDF15	ENST00000597765.2 linkuse as main transcript	c.604C>G	p.His202Asp	missense_variant	3/3	4		ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33545

AN:

152154

Hom.:

3875

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.242

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.220

GnomAD3 exomes

AF:

0.243

AC:

53675

AN:

220972

Hom.:

6693

AF XY:

0.250

AC XY:

30773

AN XY:

123056

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.174

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.259

Gnomad SAS exome

AF:

0.325

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.250

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.251

AC:

362783

AN:

1446684

Hom.:

46642

Cov.:

AF XY:

0.253

AC XY:

181921

AN XY:

719490

show subpopulations

Gnomad4 AFR exome

AF:

0.151

Gnomad4 AMR exome

AF:

0.175

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.259

Gnomad4 SAS exome

AF:

0.321

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.240

GnomAD4 genome

AF:

0.220

AC:

33545

AN:

152272

Hom.:

3873

Cov.:

AF XY:

0.220

AC XY:

16395

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.176

Gnomad4 ASJ

AF:

0.209

Gnomad4 EAS

AF:

0.263

Gnomad4 SAS

AF:

0.310

Gnomad4 FIN

AF:

0.258

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.219

Alfa

AF:

0.206

Hom.:

1049

Bravo

AF:

0.209

TwinsUK

AF:

0.261

AC:

969

ALSPAC

AF:

0.254

AC:

980

ESP6500AA

AF:

0.143

AC:

607

ESP6500EA

AF:

0.221

AC:

1845

ExAC

AF:

0.237

AC:

28149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.8

DANN

Benign

0.75

DEOGEN2

Benign

0.071

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.40

REVEL

Benign

0.037

Sift

Benign

0.49

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.033

MPC

0.86

ClinPred

0.00030

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.14

gMVP

0.61

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