rs1555823599

Variant names:

• chr20-35438202-CG-C
• rs1555823599
• NM_000557.5:c.-275delC

Variant summary

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

The NM_000557.5(GDF5):​c.-275delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 381,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: GDF5 NM_000557.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• 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 Gene-Disease associations (from GenCC):

• brachydactyly type C

  Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• symphalangism, proximal, 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acromesomelic dysplasia 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• brachydactyly type A1C

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Angel-shaped phalango-epiphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• brachydactyly type A1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• brachydactyly type A2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple synostoses syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• proximal symphalangism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromesomelic dysplasia 2B

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• acromesomelic dysplasia 2C, Hunter-Thompson type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-275delC		5_prime_UTR	Exon 1 of 2	NP_000548.2
	GDF5	NM_001319138.2		c.-241-34delC		intron	N/A	NP_001306067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	ENST00000374369.8	TSL:1 MANE Select	c.-275delC		5_prime_UTR	Exon 1 of 2	ENSP00000363489.3
	GDF5	ENST00000374372.1	TSL:1	c.-241-34delC		intron	N/A	ENSP00000363492.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000262 AC: 1 AN: 381844 Hom.: 0 Cov.: 3 AF XY: 0.00000496 AC XY: 1 AN XY: 201616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10890

American (AMR) AF: 0.00 AC: 0 AN: 16728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11790

East Asian (EAS) AF: 0.00 AC: 0 AN: 25426

South Asian (SAS) AF: 0.0000237 AC: 1 AN: 42130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228088

Other (OTH) AF: 0.00 AC: 0 AN: 22192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

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: rs1555823599; hg19: chr20-34025982;