rs224333

Positions:

• chr20-35436182-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000557.5(GDF5):​c.631+1116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 151,984 control chromosomes in the GnomAD database, including 21,150 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (21150 hom., cov: 31)
• Consequence: GDF5 NM_000557.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.631+1116T>C		intron_variant		ENST00000374369.8
GDF5	NM_001319138.2	c.631+1116T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.631+1116T>C		intron_variant		1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.631+1116T>C		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72479 AN: 151866 Hom.: 21147 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.477 AC: 72472 AN: 151984 Hom.: 21150 Cov.: 31 AF XY: 0.478 AC XY: 35528 AN XY: 74294

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.719

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.501

Alfa AF: 0.522 Hom.: 3764

Bravo AF: 0.472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs224333; hg19: chr20-34023962;