rs143383

Positions:

• chr20-35438203-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000557.5(GDF5):​c.-275C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 515,694 control chromosomes in the GnomAD database, including 87,096 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 (21156 hom., cov: 30)
  • Exomes 𝑓: 0.59 (65940 hom.)
• Consequence: GDF5 NM_000557.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF5	NM_000557.5	c.-275C>T		5_prime_UTR_variant	1/2	ENST00000374369.8	NP_000548.2
GDF5	NM_001319138.2	c.-241-34C>T		intron_variant			NP_001306067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8	c.-275C>T		5_prime_UTR_variant	1/2	1	NM_000557.5	ENSP00000363489	P1
GDF5	ENST00000374372.1	c.-241-34C>T		intron_variant		1		ENSP00000363492	P1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72469 AN: 151770 Hom.: 21153 Cov.: 30

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.590 AC: 214796 AN: 363806 Hom.: 65940 Cov.: 3 AF XY: 0.583 AC XY: 111720 AN XY: 191776

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.683

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.748

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.621

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.477 AC: 72461 AN: 151888 Hom.: 21156 Cov.: 30 AF XY: 0.478 AC XY: 35512 AN XY: 74224

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.440

Gnomad4 FIN AF: 0.585

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.509

Alfa AF: 0.608 Hom.: 40102

Bravo AF: 0.473

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
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: rs143383; hg19: chr20-34025983;