rs224334

Variant names:

• chr20-35436939-A-G
• rs224334
• NM_000557.5:c.631+359T>C

Variant summary

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

The NM_000557.5(GDF5):​c.631+359T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 152,264 control chromosomes in the GnomAD database, including 64,843 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 0.92 (64843 hom., cov: 32)
• Consequence: GDF5 NM_000557.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114
• Publications: 9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• acromesomelic dysplasia 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.941 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+359T>C		intron	N/A	NP_000548.2	P43026
	GDF5	NM_001319138.2		c.631+359T>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+359T>C		intron	N/A	ENSP00000363489.3	P43026
	GDF5	ENST00000374372.1	TSL:1	c.631+359T>C		intron	N/A	ENSP00000363492.1	P43026
	GDF5	ENST00000968510.1		c.631+359T>C		intron	N/A	ENSP00000638569.1

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140273 AN: 152146 Hom.: 64823 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.951

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.923

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.922 AC: 140341 AN: 152264 Hom.: 64843 Cov.: 32 AF XY: 0.920 AC XY: 68508 AN XY: 74450

African (AFR) AF: 0.891 AC: 36995 AN: 41538

American (AMR) AF: 0.952 AC: 14556 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3223 AN: 3472

East Asian (EAS) AF: 0.828 AC: 4290 AN: 5184

South Asian (SAS) AF: 0.791 AC: 3815 AN: 4824

European-Finnish (FIN) AF: 0.938 AC: 9957 AN: 10614

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64408 AN: 68018

Other (OTH) AF: 0.915 AC: 1933 AN: 2112

Alfa AF: 0.935 Hom.: 16278

Bravo AF: 0.925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.7
PhyloP100		0.11

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs224334;

hg19: chr20-34024719;