Genetic Variant NM_004864.4:c.25G>C (chr19-18386214-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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. 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.

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

Publications

49 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GDF15	NM_004864.4 link	c.25G>C	p.Val9Leu	missense_variant	Exon 1 of 2	ENST00000252809.3	NP_004855.2	Q99988

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GDF15	ENST00000252809.3 link	c.25G>C	p.Val9Leu	missense_variant	Exon 1 of 2	1	NM_004864.4	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3 link	c.25G>C	p.Val9Leu	missense_variant	Exon 2 of 3	5		ENSP00000470531.3	Q99988A0A0A0MTT8
GDF15	ENST00000597765.2 link	c.25G>C	p.Val9Leu	missense_variant	Exon 2 of 3	4		ENSP00000469819.2	Q99988
GDF15	ENST00000604609.2 link	n.*142G>C		downstream_gene_variant		3

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

GnomAD2 exomes

AF:

0.690

AC:

172826

AN:

250524

AF XY:

0.683

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 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

African (AFR)

AF:

0.784

AC:

26183

AN:

33408

American (AMR)

AF:

0.711

AC:

31768

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

18038

AN:

26126

East Asian (EAS)

AF:

0.612

AC:

24304

AN:

39692

South Asian (SAS)

AF:

0.636

AC:

54786

AN:

86178

European-Finnish (FIN)

AF:

0.791

AC:

42180

AN:

53334

Middle Eastern (MID)

AF:

0.608

AC:

2826

AN:

4648

European-Non Finnish (NFE)

AF:

0.662

AC:

736297

AN:

1111522

Other (OTH)

AF:

0.671

AC:

40451

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

17901

35801

53702

71602

89503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19204

38408

57612

76816

96020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.709

AC:

107881

AN:

152126

Hom.:

38514

Cov.:

AF XY:

0.713

AC XY:

52999

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.778

AC:

32298

AN:

41506

American (AMR)

AF:

0.692

AC:

10582

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.707

AC:

2456

AN:

3472

East Asian (EAS)

AF:

0.659

AC:

3400

AN:

5156

South Asian (SAS)

AF:

0.626

AC:

3015

AN:

4816

European-Finnish (FIN)

AF:

0.810

AC:

8582

AN:

10598

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.667

AC:

45356

AN:

67980

Other (OTH)

AF:

0.661

AC:

1390

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1614

3228

4843

6457

8071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

0.16

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

PromoterAI

-0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over