20-35437412-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000557.5(GDF5):ā€‹c.517A>Cā€‹(p.Met173Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GDF5
NM_000557.5 missense

Scores

5
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
GDF5 (HGNC:4220): (growth differentiation factor 5) 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 regulates the development of numerous tissue and cell types, including cartilage, joints, brown fat, teeth, and the growth of neuronal axons and dendrites. Mutations in this gene are associated with acromesomelic dysplasia, brachydactyly, chondrodysplasia, multiple synostoses syndrome, proximal symphalangism, and susceptibility to osteoarthritis. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.828

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GDF5NM_000557.5 linkuse as main transcriptc.517A>C p.Met173Leu missense_variant 1/2 ENST00000374369.8 NP_000548.2 P43026F1T0J1
GDF5NM_001319138.2 linkuse as main transcriptc.517A>C p.Met173Leu missense_variant 3/4 NP_001306067.1 P43026F1T0J1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GDF5ENST00000374369.8 linkuse as main transcriptc.517A>C p.Met173Leu missense_variant 1/21 NM_000557.5 ENSP00000363489.3 P43026
GDF5ENST00000374372.1 linkuse as main transcriptc.517A>C p.Met173Leu missense_variant 3/41 ENSP00000363492.1 P43026

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251252
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135802
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461392
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
26
DANN
Benign
0.97
DEOGEN2
Benign
0.32
T;T
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Benign
0.080
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
0.077
D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-2.4
N;N
REVEL
Uncertain
0.64
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0090
D;D
Polyphen
1.0
D;D
Vest4
0.74
MutPred
0.80
Loss of phosphorylation at Y177 (P = 0.133);Loss of phosphorylation at Y177 (P = 0.133);
MVP
0.59
MPC
0.13
ClinPred
0.84
D
GERP RS
4.5
gMVP
0.70

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: rs28936397; hg19: chr20-34025192; API