rs143383

Variant names:

• chr20-35438203-G-A
• rs143383
• NM_000557.5:c.-275C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-35438203-G-A
• chr20-35438203-G-C
• chr20-35438203-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000557.5(GDF5):​c.-275C>T variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 218 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
GDF5	NM_000557.5	c.-275C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_000557.5	c.-275C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_001319138.2	c.-241-34C>T		intron_variant	Intron 2 of 3		NP_001306067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8	c.-275C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374369.8	c.-275C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374372.1	c.-241-34C>T		intron_variant	Intron 2 of 3	1		ENSP00000363492.1

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

African (AFR) AF: 0.123 AC: 1326 AN: 10808

American (AMR) AF: 0.683 AC: 11036 AN: 16152

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 6165 AN: 11204

East Asian (EAS) AF: 0.748 AC: 17858 AN: 23872

South Asian (SAS) AF: 0.450 AC: 18544 AN: 41168

European-Finnish (FIN) AF: 0.587 AC: 12518 AN: 21328

Middle Eastern (MID) AF: 0.519 AC: 819 AN: 1578

European-Non Finnish (NFE) AF: 0.621 AC: 134343 AN: 216468

Other (OTH) AF: 0.574 AC: 12187 AN: 21228

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

African (AFR) AF: 0.121 AC: 5003 AN: 41420

American (AMR) AF: 0.624 AC: 9515 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1890 AN: 3466

East Asian (EAS) AF: 0.717 AC: 3700 AN: 5160

South Asian (SAS) AF: 0.440 AC: 2121 AN: 4822

European-Finnish (FIN) AF: 0.585 AC: 6163 AN: 10534

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42304 AN: 67938

Other (OTH) AF: 0.509 AC: 1070 AN: 2104

Alfa AF: 0.573 Hom.: 63942

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
PhyloP100		2.5
PromoterAI		-0.094	Neutral

Splicing

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

Other links and lift over

dbSNP: rs143383; hg19: chr20-34025983;