chr20-35434514-G-A

Position:

• chr20-35434514-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000557.5(GDF5):​c.901C>T​(p.Arg301Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R301R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GDF5 NM_000557.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.67

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-35434514-G-A is Pathogenic according to our data. Variant chr20-35434514-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-35434514-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.901C>T	p.Arg301Ter	stop_gained	2/2	ENST00000374369.8
GDF5-AS1	NR_161326.1	n.798G>A		non_coding_transcript_exon_variant	2/2
GDF5	NM_001319138.2	c.901C>T	p.Arg301Ter	stop_gained	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.901C>T	p.Arg301Ter	stop_gained	2/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.901C>T	p.Arg301Ter	stop_gained	4/4	1		P1
GDF5-AS1	ENST00000374375.1	n.798G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453716 Hom.: 0 Cov.: 59 AF XY: 0.00000277 AC XY: 2 AN XY: 722360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 03, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GDF5 protein in which other variant(s) (p.Arg380Gln) have been determined to be pathogenic (PMID: 18203755). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change creates a premature translational stop signal (p.Arg301*) in the GDF5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 201 amino acid(s) of the GDF5 protein. ClinVar contains an entry for this variant (Variation ID: 8378). This premature translational stop signal has been observed in individual(s) with brachydactyly (PMID: 9288091). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Brachydactyly type C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1997

- -

Multiple synostoses syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 21, 2022

ACMG classification criteria: PVS1 strong, PM2 moderated -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	0.36	A;A;A
Vest4		0.76
ClinPred		1.0	D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315386; hg19: chr20-34022312; COSMIC: COSV65499324;