rs224330

Positions:

• chr20-35434398-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3 BP6_Moderate BP7 BA1

The NM_000557.5(GDF5):​c.1017A>G​(p.Lys339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,613,684 control chromosomes in the GnomAD database, including 696,211 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (61325 hom., cov: 32)
  • Exomes 𝑓: 0.93 (634886 hom.)
• Consequence: GDF5 NM_000557.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.936

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-AS1 (HGNC:33435): (GDF5 antisense RNA 1) Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.24
• BP6: Variant 20-35434398-T-C is Benign according to our data. Variant chr20-35434398-T-C is described in ClinVar as [Benign]. Clinvar id is 695733.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.936 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) 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.1017A>G	p.Lys339=	synonymous_variant	2/2	ENST00000374369.8
GDF5-AS1	NR_161326.1	n.682T>C		non_coding_transcript_exon_variant	2/2
GDF5	NM_001319138.2	c.1017A>G	p.Lys339=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.1017A>G	p.Lys339=	synonymous_variant	2/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.1017A>G	p.Lys339=	synonymous_variant	4/4	1		P1
GDF5-AS1	ENST00000374375.1	n.682T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.895 AC: 136150 AN: 152150 Hom.: 61316 Cov.: 32

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.909

GnomAD4 exome AF: 0.931 AC: 1360302 AN: 1461416 Hom.: 634886 Cov.: 81 AF XY: 0.927 AC XY: 673757 AN XY: 726990

Gnomad4 AFR exome AF: 0.790

Gnomad4 AMR exome AF: 0.956

Gnomad4 ASJ exome AF: 0.928

Gnomad4 EAS exome AF: 0.841

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.935

Gnomad4 NFE exome AF: 0.948

Gnomad4 OTH exome AF: 0.919

GnomAD4 genome AF: 0.894 AC: 136202 AN: 152268 Hom.: 61325 Cov.: 32 AF XY: 0.893 AC XY: 66488 AN XY: 74452

Gnomad4 AFR AF: 0.795

Gnomad4 AMR AF: 0.944

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.828

Gnomad4 SAS AF: 0.789

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.901

Alfa AF: 0.935 Hom.: 85549

Bravo AF: 0.895

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	15

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs224330; hg19: chr20-34022196;