rs143384

chr20-35437976-G-A

Variant summary

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

The NM_000557.5(GDF5):c.-48C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.559 in 1,608,156 control chromosomes in the GnomAD database, including 262,325 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 0.45 (18724 hom., cov: 31)
  • Exomes 𝑓: 0.57 (243601 hom.)
• Consequence: GDF5 NM_000557.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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=-0.46).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.-48C>T		5_prime_UTR_variant	1/2	ENST00000374369.8
GDF5	NM_001319138.2	c.-48C>T		5_prime_UTR_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.-48C>T		5_prime_UTR_variant	1/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.-48C>T		5_prime_UTR_variant	3/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68078 AN: 151870 Hom.: 18724 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.476

GnomAD4 exome AF: 0.570 AC: 830651 AN: 1456168 Hom.: 243601 Cov.: 35 AF XY: 0.566 AC XY: 410041 AN XY: 724028

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.688

Gnomad4 ASJ exome AF: 0.496

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.558

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.549

GnomAD4 genome AF: 0.448 AC: 68069 AN: 151988 Hom.: 18724 Cov.: 31 AF XY: 0.450 AC XY: 33437 AN XY: 74274

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.602

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.558

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.471

Alfa AF: 0.558 Hom.: 39289

Bravo AF: 0.443

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143384; hg19: chr20-34025756;