Genetic Variant GDF15:c.*70G>C (chr19-18389005-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.*70G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,072,570 control chromosomes in the GnomAD database, including 10,156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1111 hom., cov: 32)

Exomes 𝑓: 0.13 ( 9045 hom. )

Consequence

GDF15
NM_004864.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.849

Publications

43 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 (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF15	NM_004864.4 link	c.*70G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000252809.3	NP_004855.2	Q99988

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GDF15	ENST00000252809.3 link	c.*70G>C	3_prime_UTR_variant	Exon 2 of 2	1	NM_004864.4	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3 link	c.*70G>C	downstream_gene_variant		5		ENSP00000470531.3	Q99988A0A0A0MTT8
GDF15	ENST00000597765.2 link	c.*70G>C	downstream_gene_variant		4		ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16702

AN:

152148

Hom.:

1112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0461

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.154

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.145

GnomAD4 exome

AF:

0.135

AC:

124035

AN:

920304

Hom.:

9045

Cov.:

AF XY:

0.135

AC XY:

62680

AN XY:

464434

show subpopulations

African (AFR)

AF:

0.0416

AC:

901

AN:

21656

American (AMR)

AF:

0.125

AC:

3780

AN:

30132

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

2924

AN:

17682

East Asian (EAS)

AF:

0.196

AC:

6963

AN:

35446

South Asian (SAS)

AF:

0.104

AC:

6165

AN:

59406

European-Finnish (FIN)

AF:

0.0766

AC:

2666

AN:

34798

Middle Eastern (MID)

AF:

0.137

AC:

570

AN:

4146

European-Non Finnish (NFE)

AF:

0.140

AC:

94400

AN:

675224

Other (OTH)

AF:

0.136

AC:

5666

AN:

41814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

5461

10922

16384

21845

27306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2860

5720

8580

11440

14300

<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:

0.110

AC:

16700

AN:

152266

Hom.:

1111

Cov.:

AF XY:

0.108

AC XY:

8069

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0461

AC:

1917

AN:

41556

American (AMR)

AF:

0.139

AC:

2125

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.154

AC:

533

AN:

3468

East Asian (EAS)

AF:

0.170

AC:

883

AN:

5188

South Asian (SAS)

AF:

0.100

AC:

484

AN:

4826

European-Finnish (FIN)

AF:

0.0734

AC:

778

AN:

10594

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9493

AN:

68032

Other (OTH)

AF:

0.144

AC:

305

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

744

1488

2232

2976

3720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.119

Hom.:

157

Bravo

AF:

0.113

Asia WGS

AF:

0.110

AC:

382

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.85

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

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