19-18388375-G-C

Variant names:

• chr19-18388375-G-C
• rs999689035
• NM_004864.4:c.367G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004864.4(GDF15):​c.367G>C​(p.Ala123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GDF15 NM_004864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF15	NM_004864.4	c.367G>C	p.Ala123Pro	missense_variant	Exon 2 of 2	ENST00000252809.3	NP_004855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF15	ENST00000252809.3	c.367G>C	p.Ala123Pro	missense_variant	Exon 2 of 2	1	NM_004864.4	ENSP00000252809.3
GDF15	ENST00000595973.3	c.367G>C	p.Ala123Pro	missense_variant	Exon 3 of 3	5		ENSP00000470531.3
GDF15	ENST00000597765.2	c.367G>C	p.Ala123Pro	missense_variant	Exon 3 of 3	4		ENSP00000469819.2
GDF15	ENST00000594925.1	n.185G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459390 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726016

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367G>C (p.A123P) alteration is located in exon 2 (coding exon 2) of the GDF15 gene. This alteration results from a G to C substitution at nucleotide position 367, causing the alanine (A) at amino acid position 123 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.28		Loss of MoRF binding (P = 0.0617);
MVP		0.85
MPC		1.8
ClinPred		0.83	D
GERP RS		3.2
Varity_R		0.61
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs999689035; hg19: chr19-18499185;