20-35434589-C-G

Variant names:

• chr20-35434589-C-G
• rs224331
• NM_000557.5:c.826G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000557.5(GDF5):​c.826G>C​(p.Ala276Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A276S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GDF5 NM_000557.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2408492).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000557.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	NM_000557.5	MANE Select	c.826G>C	p.Ala276Pro	missense	Exon 2 of 2	NP_000548.2
	GDF5	NM_001319138.2		c.826G>C	p.Ala276Pro	missense	Exon 4 of 4	NP_001306067.1
	GDF5-AS1	NR_161326.1		n.873C>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	ENST00000374369.8	TSL:1 MANE Select	c.826G>C	p.Ala276Pro	missense	Exon 2 of 2	ENSP00000363489.3
	GDF5	ENST00000374372.1	TSL:1	c.826G>C	p.Ala276Pro	missense	Exon 4 of 4	ENSP00000363492.1
	GDF5-AS1	ENST00000374375.1	TSL:2	n.873C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432378 Hom.: 0 Cov.: 53 AF XY: 0.00 AC XY: 0 AN XY: 708672

African (AFR) AF: 0.00 AC: 0 AN: 32404

American (AMR) AF: 0.00 AC: 0 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24418

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095610

Other (OTH) AF: 0.00 AC: 0 AN: 58796

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DEOGEN2	Benign	0.23	T
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.24	T
PhyloP100		2.5
Sift4G	Benign	0.27	T
Vest4		0.27
gMVP		0.81

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

Other links and lift over

dbSNP: rs224331; hg19: chr20-34022387;