NM_000557.5:c.-48C>T

Variant names:

• chr20-35437976-G-A
• rs143384
• NM_000557.5:c.-48C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000557.5(GDF5):​c.-48C>T variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 186 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 -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 rank	MANE	Protein	UniProt
GDF5	NM_000557.5	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_000557.5	c.-48C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_001319138.2	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 4		NP_001306067.1
GDF5	NM_001319138.2	c.-48C>T		5_prime_UTR_variant	Exon 3 of 4		NP_001306067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374372.1	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 4	1		ENSP00000363492.1
GDF5	ENST00000374369.8	c.-48C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374372.1	c.-48C>T		5_prime_UTR_variant	Exon 3 of 4	1		ENSP00000363492.1

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

African (AFR) AF: 0.0928 AC: 3094 AN: 33338

American (AMR) AF: 0.688 AC: 30367 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12909 AN: 26044

East Asian (EAS) AF: 0.744 AC: 29499 AN: 39636

South Asian (SAS) AF: 0.427 AC: 36511 AN: 85584

European-Finnish (FIN) AF: 0.558 AC: 29611 AN: 53110

Middle Eastern (MID) AF: 0.471 AC: 2541 AN: 5400

European-Non Finnish (NFE) AF: 0.589 AC: 653119 AN: 1108780

Other (OTH) AF: 0.549 AC: 33000 AN: 60148

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

African (AFR) AF: 0.113 AC: 4696 AN: 41492

American (AMR) AF: 0.602 AC: 9170 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1687 AN: 3472

East Asian (EAS) AF: 0.716 AC: 3693 AN: 5158

South Asian (SAS) AF: 0.425 AC: 2046 AN: 4818

European-Finnish (FIN) AF: 0.558 AC: 5884 AN: 10542

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39337 AN: 67960

Other (OTH) AF: 0.471 AC: 990 AN: 2102

Alfa AF: 0.541 Hom.: 84586

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
PhyloP100		3.7
PromoterAI		-0.037	Neutral

Splicing

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

Other links and lift over

dbSNP: rs143384; hg19: chr20-34025756;