rs224331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.61 ( 28997 hom., cov: 31)

Exomes 𝑓: 0.65 ( 299590 hom. )

Consequence

GDF5
NM_000557.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.45

Variant links:

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 links:

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

GDF5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GDF5	NM_000557.5 link	c.826G>T	p.Ala276Ser	missense_variant	Exon 2 of 2	ENST00000374369.8	NP_000548.2	P43026F1T0J1
GDF5	NM_001319138.2 link	c.826G>T	p.Ala276Ser	missense_variant	Exon 4 of 4		NP_001306067.1	P43026F1T0J1
GDF5-AS1	NR_161326.1 link	n.873C>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GDF5	ENST00000374369.8 link	c.826G>T	p.Ala276Ser	missense_variant	Exon 2 of 2	1	NM_000557.5	ENSP00000363489.3	P43026
GDF5	ENST00000374372.1 link	c.826G>T	p.Ala276Ser	missense_variant	Exon 4 of 4	1		ENSP00000363492.1	P43026
GDF5-AS1	ENST00000374375.1 link	n.873C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.615

AC:

93443

AN:

151896

Hom.:

28993

Cov.:

show subpopulations

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.:

AF XY:

0.641

AC XY:

454088

AN XY:

708580

show subpopulations

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.:

AF XY:

0.614

AC XY:

45598

AN XY:

74294

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_noAF

Benign

-0.50

CADD

Benign

DEOGEN2

Benign

0.21

T;T

LIST_S2

Benign

0.47

.;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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over