19-18376857-C-T

Variant names:

• chr19-18376857-C-T
• rs78015699
• ENST00000597765.2:c.-274+1857C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000597765.2(GDF15):​c.-274+1857C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 152,008 control chromosomes in the GnomAD database, including 40 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 0.021 (40 hom., cov: 31)
• Consequence: GDF15 ENST00000597765.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 7 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=-0.96).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0205 (3120/152008) while in subpopulation SAS AF = 0.0487 (234/4808). AF 95% confidence interval is 0.0436. There are 40 homozygotes in GnomAd4. There are 1603 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000597765.2. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF15	ENST00000597765.2	TSL:4	c.-274+1857C>T		intron	N/A	ENSP00000469819.2
	GDF15	ENST00000604609.2	TSL:3	n.252+1854C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3121 AN: 151890 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.00537

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0144

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

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152008 Hom.: 40 Cov.: 31 AF XY: 0.0216 AC XY: 1603 AN XY: 74318

African (AFR) AF: 0.00535 AC: 222 AN: 41480

American (AMR) AF: 0.0135 AC: 206 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3468

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.0487 AC: 234 AN: 4808

European-Finnish (FIN) AF: 0.0454 AC: 479 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1882 AN: 67978

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0242 Hom.: 4

Bravo AF: 0.0167

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.061
DANN	Benign	0.54
PhyloP100		-2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78015699; hg19: chr19-18487667;