rs224330

Variant names:

• chr20-35434398-T-C
• rs224330
• NM_000557.5:c.1017A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP6_Moderate BP7 BA1

The NM_000557.5(GDF5):​c.1017A>G​(p.Lys339Lys) 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
• Publications: 20 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-AS1 (HGNC:33435): (GDF5 antisense RNA 1) Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GDF5	NM_000557.5	c.1017A>G	p.Lys339Lys	synonymous_variant	Exon 2 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_001319138.2	c.1017A>G	p.Lys339Lys	synonymous_variant	Exon 4 of 4		NP_001306067.1
GDF5-AS1	NR_161326.1	n.682T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8	c.1017A>G	p.Lys339Lys	synonymous_variant	Exon 2 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374372.1	c.1017A>G	p.Lys339Lys	synonymous_variant	Exon 4 of 4	1		ENSP00000363492.1
GDF5-AS1	ENST00000374375.1	n.682T>C		non_coding_transcript_exon_variant	Exon 2 of 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

African (AFR) AF: 0.790 AC: 26455 AN: 33480

American (AMR) AF: 0.956 AC: 42770 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 24244 AN: 26136

East Asian (EAS) AF: 0.841 AC: 33372 AN: 39700

South Asian (SAS) AF: 0.795 AC: 68535 AN: 86258

European-Finnish (FIN) AF: 0.935 AC: 49514 AN: 52978

Middle Eastern (MID) AF: 0.923 AC: 5323 AN: 5768

European-Non Finnish (NFE) AF: 0.948 AC: 1054571 AN: 1111986

Other (OTH) AF: 0.919 AC: 55518 AN: 60386

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

African (AFR) AF: 0.795 AC: 33013 AN: 41538

American (AMR) AF: 0.944 AC: 14458 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3222 AN: 3470

East Asian (EAS) AF: 0.828 AC: 4269 AN: 5158

South Asian (SAS) AF: 0.789 AC: 3810 AN: 4830

European-Finnish (FIN) AF: 0.938 AC: 9964 AN: 10620

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64401 AN: 68026

Other (OTH) AF: 0.901 AC: 1905 AN: 2114

Alfa AF: 0.931 Hom.: 103219

Bravo AF: 0.895

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	15
PhyloP100		0.94

Splicing

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

Other links and lift over

dbSNP: rs224330; hg19: chr20-34022196;