19-18388465-C-T

Variant names:

• chr19-18388465-C-T
• rs1483942184
• NM_004864.4:c.457C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004864.4(GDF15):​c.457C>T​(p.Pro153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.645
• Publications: 0 publications found

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]

ACMG classification

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=0.20861468).

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.457C>T	p.Pro153Ser	missense	Exon 2 of 2	NP_004855.2	Q99988

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF15	ENST00000252809.3	TSL:1 MANE Select	c.457C>T	p.Pro153Ser	missense	Exon 2 of 2	ENSP00000252809.3	Q99988
	GDF15	ENST00000595973.3	TSL:5	c.457C>T	p.Pro153Ser	missense	Exon 3 of 3	ENSP00000470531.3	Q99988
	GDF15	ENST00000597765.2	TSL:4	c.457C>T	p.Pro153Ser	missense	Exon 3 of 3	ENSP00000469819.2	Q99988

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456350 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 724596

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49754

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111080

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.65
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.23
Sift	Benign	0.20	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.085
MutPred		0.22		Gain of phosphorylation at P153 (P = 0.0298)
MVP		0.75
MPC		0.69
ClinPred		0.53	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.048
gMVP		0.64
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1483942184; hg19: chr19-18499275;