chr19-18387998-T-G

Variant names:

• chr19-18387998-T-G
• rs1227732
• NM_004864.4:c.278-288T>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.278-288T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 151,478 control chromosomes in the GnomAD database, including 51,469 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 0.82 (51469 hom., cov: 27)
• Consequence: GDF15 NM_004864.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.424
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF15	NM_004864.4	c.278-288T>G		intron_variant	Intron 1 of 1	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000252809.3	c.278-288T>G		intron_variant	Intron 1 of 1	1	NM_004864.4	ENSP00000252809.3
GDF15	ENST00000595973.3	c.278-288T>G		intron_variant	Intron 2 of 2	5		ENSP00000470531.3
GDF15	ENST00000597765.2	c.278-288T>G		intron_variant	Intron 2 of 2	4		ENSP00000469819.2
GDF15	ENST00000594925.1	n.96-288T>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.824 AC: 124686 AN: 151360 Hom.: 51434 Cov.: 27

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.811

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.824 AC: 124778 AN: 151478 Hom.: 51469 Cov.: 27 AF XY: 0.825 AC XY: 61079 AN XY: 74006

African (AFR) AF: 0.842 AC: 34679 AN: 41172

American (AMR) AF: 0.834 AC: 12684 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2965 AN: 3464

East Asian (EAS) AF: 0.827 AC: 4247 AN: 5134

South Asian (SAS) AF: 0.726 AC: 3478 AN: 4792

European-Finnish (FIN) AF: 0.883 AC: 9287 AN: 10520

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54760 AN: 67874

Other (OTH) AF: 0.805 AC: 1694 AN: 2104

Alfa AF: 0.792 Hom.: 2787

Bravo AF: 0.823

Asia WGS AF: 0.770 AC: 2682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.6
DANN	Benign	0.92
PhyloP100		-0.42
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: rs1227732; hg19: chr19-18498808;