rs1059369

Variant names:

• chr19-18386331-T-A
• rs1059369
• NM_004864.4:c.142T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18386331-T-A
• chr19-18386331-T-C
• chr19-18386331-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 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 0.24 (4733 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43849 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 58 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]

MIR3189 (HGNC:38307): (microRNA 3189) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF15	NM_004864.4	MANE Select	c.142T>A	p.Ser48Thr	missense	Exon 1 of 2	NP_004855.2
	MIR3189	NR_036156.1		n.-231T>A		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF15	ENST00000252809.3	TSL:1 MANE Select	c.142T>A	p.Ser48Thr	missense	Exon 1 of 2	ENSP00000252809.3
	GDF15	ENST00000595973.3	TSL:5	c.142T>A	p.Ser48Thr	missense	Exon 2 of 3	ENSP00000470531.3
	GDF15	ENST00000597765.2	TSL:4	c.142T>A	p.Ser48Thr	missense	Exon 2 of 3	ENSP00000469819.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36599 AN: 151936 Hom.: 4727 Cov.: 32

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

GnomAD2 exomes AF: 0.273 AC: 68427 AN: 250812 AF XY: 0.265

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 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.: 37 AF XY: 0.238 AC XY: 173029 AN XY: 727146

African (AFR) AF: 0.168 AC: 5641 AN: 33478

American (AMR) AF: 0.403 AC: 18018 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6497 AN: 26134

East Asian (EAS) AF: 0.348 AC: 13815 AN: 39692

South Asian (SAS) AF: 0.204 AC: 17594 AN: 86254

European-Finnish (FIN) AF: 0.324 AC: 17289 AN: 53350

Middle Eastern (MID) AF: 0.175 AC: 1012 AN: 5768

European-Non Finnish (NFE) AF: 0.231 AC: 256633 AN: 1111918

Other (OTH) AF: 0.239 AC: 14454 AN: 60388

GnomAD4 genome AF: 0.241 AC: 36639 AN: 152054 Hom.: 4733 Cov.: 32 AF XY: 0.246 AC XY: 18285 AN XY: 74306

African (AFR) AF: 0.181 AC: 7508 AN: 41458

American (AMR) AF: 0.348 AC: 5313 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3472

East Asian (EAS) AF: 0.384 AC: 1984 AN: 5162

South Asian (SAS) AF: 0.198 AC: 953 AN: 4814

European-Finnish (FIN) AF: 0.336 AC: 3549 AN: 10562

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15720 AN: 67996

Other (OTH) AF: 0.223 AC: 470 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.7
DANN	Benign	0.96
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.21
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.24
Sift	Benign	0.11	T
Sift4G	Uncertain	0.046	D
Polyphen		0.68	P
Vest4		0.062
MPC		0.81
ClinPred		0.0035	T
GERP RS		-4.9
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs1059369; hg19: chr19-18497141; COSMIC: COSV53250556; COSMIC: COSV53250556;