Genetic Variant GDF15:p.His102Asn (chr19-18388312-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004864.4(GDF15):c.304C>A(p.His102Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GDF15
NM_004864.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.823

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2091946).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF15	NM_004864.4	MANE Select	c.304C>A	p.His102Asn	missense	Exon 2 of 2	NP_004855.2	Q99988

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDF15	ENST00000252809.3	TSL:1 MANE Select	c.304C>A	p.His102Asn	missense	Exon 2 of 2	ENSP00000252809.3	Q99988
GDF15	ENST00000595973.3	TSL:5	c.304C>A	p.His102Asn	missense	Exon 3 of 3	ENSP00000470531.3	Q99988
GDF15	ENST00000597765.2	TSL:4	c.304C>A	p.His102Asn	missense	Exon 3 of 3	ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000413

AC:

AN:

242028

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111730

Other (OTH)

AF:

0.0000166

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.10

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.098

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.63

PhyloP100

0.82

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.0

REVEL

Benign

0.18

Sift

Benign

0.095

Sift4G

Benign

0.57

Polyphen

0.99

Vest4

0.30

MutPred

0.23

Gain of MoRF binding (P = 0.0961)

MVP

0.79

MPC

0.69

ClinPred

0.21

GERP RS

3.0

Varity_R

0.19

gMVP

0.64

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over