rs224334

Positions:

• chr20-35436939-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.631+359T>C		intron_variant		ENST00000374369.8
GDF5	NM_001319138.2	c.631+359T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.631+359T>C		intron_variant		1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.631+359T>C		intron_variant		1		P1

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

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.952

Gnomad4 ASJ AF: 0.928

Gnomad4 EAS AF: 0.828

Gnomad4 SAS AF: 0.791

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.915

Alfa AF: 0.937 Hom.: 13966

Bravo AF: 0.925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs224334; hg19: chr20-34024719;