rs121909349

Positions:

• chr20-35434297-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000557.5(GDF5):​c.1118T>G​(p.Leu373Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDF5 NM_000557.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.43

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]

GDF5-AS1 (HGNC:33435): (GDF5 antisense RNA 1) Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000557.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• PP5: Variant 20-35434297-A-C is Pathogenic according to our data. Variant chr20-35434297-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8392.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.1118T>G	p.Leu373Arg	missense_variant	2/2	ENST00000374369.8
GDF5-AS1	NR_161326.1	n.581A>C		non_coding_transcript_exon_variant	2/2
GDF5	NM_001319138.2	c.1118T>G	p.Leu373Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.1118T>G	p.Leu373Arg	missense_variant	2/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.1118T>G	p.Leu373Arg	missense_variant	4/4	1		P1
GDF5-AS1	ENST00000374375.1	n.581A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Symphalangism, proximal, 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.069
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.12	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.71	P;P
Vest4		0.72
MutPred		0.77		Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);
MVP		0.96
MPC		1.2
ClinPred		0.68	D
GERP RS		4.3
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909349; hg19: chr20-34022095;