rs224331

Variant names:

• chr20-35434589-C-A
• rs224331
• NM_000557.5:c.826G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-35434589-C-A
• chr20-35434589-C-G
• chr20-35434589-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000557.5(GDF5):​c.826G>T​(p.Ala276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,584,228 control chromosomes in the GnomAD database, including 328,587 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28997 hom., cov: 31)
  • Exomes 𝑓: 0.65 (299590 hom.)
• Consequence: GDF5 NM_000557.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.45
• Publications: 60 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003421843).
• BP6: Variant 20-35434589-C-A is Benign according to our data. Variant chr20-35434589-C-A is described in ClinVar as Benign. ClinVar VariationId is 695737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	NM_000557.5	MANE Select	c.826G>T	p.Ala276Ser	missense	Exon 2 of 2	NP_000548.2
	GDF5	NM_001319138.2		c.826G>T	p.Ala276Ser	missense	Exon 4 of 4	NP_001306067.1
	GDF5-AS1	NR_161326.1		n.873C>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF5	ENST00000374369.8	TSL:1 MANE Select	c.826G>T	p.Ala276Ser	missense	Exon 2 of 2	ENSP00000363489.3
	GDF5	ENST00000374372.1	TSL:1	c.826G>T	p.Ala276Ser	missense	Exon 4 of 4	ENSP00000363492.1
	GDF5-AS1	ENST00000374375.1	TSL:2	n.873C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93443 AN: 151896 Hom.: 28993 Cov.: 31

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.620

GnomAD4 exome AF: 0.645 AC: 923855 AN: 1432214 Hom.: 299590 Cov.: 53 AF XY: 0.641 AC XY: 454088 AN XY: 708580

African (AFR) AF: 0.547 AC: 17718 AN: 32404

American (AMR) AF: 0.764 AC: 31830 AN: 41682

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 14162 AN: 24416

East Asian (EAS) AF: 0.746 AC: 29253 AN: 39214

South Asian (SAS) AF: 0.541 AC: 44753 AN: 82712

European-Finnish (FIN) AF: 0.606 AC: 31462 AN: 51904

Middle Eastern (MID) AF: 0.580 AC: 3257 AN: 5616

European-Non Finnish (NFE) AF: 0.652 AC: 713943 AN: 1095474

Other (OTH) AF: 0.637 AC: 37477 AN: 58792

GnomAD4 genome AF: 0.615 AC: 93469 AN: 152014 Hom.: 28997 Cov.: 31 AF XY: 0.614 AC XY: 45598 AN XY: 74294

African (AFR) AF: 0.546 AC: 22637 AN: 41464

American (AMR) AF: 0.693 AC: 10602 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1982 AN: 3464

East Asian (EAS) AF: 0.720 AC: 3688 AN: 5122

South Asian (SAS) AF: 0.530 AC: 2554 AN: 4820

European-Finnish (FIN) AF: 0.598 AC: 6336 AN: 10588

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.642 AC: 43639 AN: 67952

Other (OTH) AF: 0.613 AC: 1295 AN: 2112

Alfa AF: 0.637 Hom.: 38621

Bravo AF: 0.625

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DEOGEN2	Benign	0.21	T
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0034	T
PhyloP100		2.5
Sift4G	Benign	0.72	T
Vest4		0.066
gMVP		0.32

Splicing

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

Other links and lift over

dbSNP: rs224331; hg19: chr20-34022387;