12-7690080-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020634.3(GDF3):​c.893C>G​(p.Pro298Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

GDF3
NM_020634.3 missense

Scores

9
8
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.98
Variant links:
Genes affected
GDF3 (HGNC:4218): (growth differentiation factor 3) 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. This protein plays a role ocular and skeletal development. Mutations in this gene are associated with microphthalmia, coloboma, and skeletal abnormalities in human patients. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GDF3NM_020634.3 linkc.893C>G p.Pro298Arg missense_variant Exon 2 of 2 ENST00000329913.4 NP_065685.1 Q9NR23

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GDF3ENST00000329913.4 linkc.893C>G p.Pro298Arg missense_variant Exon 2 of 2 1 NM_020634.3 ENSP00000331745.3 Q9NR23

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.037
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.83
MutPred
0.77
Loss of glycosylation at S300 (P = 0.0598);
MVP
0.94
MPC
0.55
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.83
gMVP
0.82

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1864109147; hg19: chr12-7842676; API