rs224331

chr20-35434589-C-Achr20-35434589-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.826G>T	p.Ala276Ser	missense_variant	2/2	ENST00000374369.8
GDF5-AS1	NR_161326.1	n.873C>A		non_coding_transcript_exon_variant	2/2
GDF5	NM_001319138.2	c.826G>T	p.Ala276Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.826G>T	p.Ala276Ser	missense_variant	2/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.826G>T	p.Ala276Ser	missense_variant	4/4	1		P1
GDF5-AS1	ENST00000374375.1	n.873C>A		non_coding_transcript_exon_variant	2/2	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

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.764

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.746

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.606

Gnomad4 NFE exome AF: 0.652

Gnomad4 OTH exome AF: 0.637

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

Gnomad4 AFR AF: 0.546

Gnomad4 AMR AF: 0.693

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.598

Gnomad4 NFE AF: 0.642

Gnomad4 OTH AF: 0.613

Alfa AF: 0.639 Hom.: 29914

Bravo AF: 0.625

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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
AlphaMissense	Benign	0.28
BayesDel_noAF	Benign	-0.50
Cadd	Benign	21
DEOGEN2	Benign	0.21	T;T
MetaRNN	Benign	0.0034	T;T
Sift4G	Benign	0.72	T;T
Vest4		0.066
gMVP		0.32

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs224331; hg19: chr20-34022387;