rs224333

Variant names:

• chr20-35436182-A-G
• rs224333
• NM_000557.5:c.631+1116T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 61 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• acromesomelic dysplasia 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	NM_000557.5	MANE Select	c.631+1116T>C		intron	N/A	NP_000548.2	P43026
	GDF5	NM_001319138.2		c.631+1116T>C		intron	N/A	NP_001306067.1	P43026

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	ENST00000374369.8	TSL:1 MANE Select	c.631+1116T>C		intron	N/A	ENSP00000363489.3	P43026
	GDF5	ENST00000374372.1	TSL:1	c.631+1116T>C		intron	N/A	ENSP00000363492.1	P43026
	GDF5	ENST00000968510.1		c.631+1116T>C		intron	N/A	ENSP00000638569.1

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

African (AFR) AF: 0.121 AC: 5009 AN: 41444

American (AMR) AF: 0.627 AC: 9567 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1886 AN: 3470

East Asian (EAS) AF: 0.719 AC: 3721 AN: 5174

South Asian (SAS) AF: 0.439 AC: 2113 AN: 4818

European-Finnish (FIN) AF: 0.586 AC: 6205 AN: 10580

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.622 AC: 42225 AN: 67936

Other (OTH) AF: 0.501 AC: 1056 AN: 2106

Alfa AF: 0.556 Hom.: 38078

Bravo AF: 0.472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs224333; hg19: chr20-34023962;