Variant rs1059369 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.142T>A(p.Ser48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,728 control chromosomes in the GnomAD database, including 48,582 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 0.24 ( 4733 hom., cov: 32)

Exomes 𝑓: 0.24 ( 43849 hom. )

Consequence

GDF15
NM_004864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.215

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=0.0019753575).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 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.142T>A	p.Ser48Thr	missense_variant	1/2	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GDF15	ENST00000252809.3 linkuse as main transcript	c.142T>A	p.Ser48Thr	missense_variant	1/2	1	NM_004864.4	ENSP00000252809	P1
GDF15	ENST00000595973.3 linkuse as main transcript	c.142T>A	p.Ser48Thr	missense_variant	2/3	5		ENSP00000470531	P1
GDF15	ENST00000597765.2 linkuse as main transcript	c.142T>A	p.Ser48Thr	missense_variant	2/3	4		ENSP00000469819	P1

Frequencies

GnomAD3 genomes

AF:

0.241

AC:

36599

AN:

151936

Hom.:

4727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.231

Gnomad OTH

AF:

0.224

GnomAD3 exomes

AF:

0.273

AC:

68427

AN:

250812

Hom.:

10237

AF XY:

0.265

AC XY:

35959

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.389

Gnomad SAS exome

AF:

0.202

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.240

AC:

350953

AN:

1461674

Hom.:

43849

Cov.:

AF XY:

0.238

AC XY:

173029

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.168

Gnomad4 AMR exome

AF:

0.403

Gnomad4 ASJ exome

AF:

0.249

Gnomad4 EAS exome

AF:

0.348

Gnomad4 SAS exome

AF:

0.204

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.231

Gnomad4 OTH exome

AF:

0.239

GnomAD4 genome

AF:

0.241

AC:

36639

AN:

152054

Hom.:

4733

Cov.:

AF XY:

0.246

AC XY:

18285

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.181

Gnomad4 AMR

AF:

0.348

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.384

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.336

Gnomad4 NFE

AF:

0.231

Gnomad4 OTH

AF:

0.223

Alfa

AF:

0.221

Hom.:

3009

Bravo

AF:

0.242

TwinsUK

AF:

0.225

AC:

835

ALSPAC

AF:

0.234

AC:

902

ESP6500AA

AF:

0.182

AC:

803

ESP6500EA

AF:

0.238

AC:

2049

ExAC

AF:

0.263

AC:

31984

Asia WGS

AF:

0.282

AC:

980

AN:

3478

EpiCase

AF:

0.219

EpiControl

AF:

0.228

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.7

DANN

Benign

0.96

DEOGEN2

Benign

0.093

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.74

.;N

REVEL

Benign

0.24

Sift

Benign

0.11

.;T

Sift4G

Uncertain

0.046

D;T

Polyphen

0.68

.;P

Vest4

0.062

MPC

0.81

ClinPred

0.0035

GERP RS

-4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.23

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