20-35433484-A-G

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.*425T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 338,590 control chromosomes in the GnomAD database, including 1,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (369 hom., cov: 32)
  • Exomes 𝑓: 0.087 (1193 hom.)
• Consequence: GDF5 NM_000557.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.243

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 (BayesDel_noAF=-0.86).
• BP6: Variant 20-35433484-A-G is Benign according to our data. Variant chr20-35433484-A-G is described in ClinVar as [Benign]. Clinvar id is 338310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF5	NM_000557.5	c.*425T>C		3_prime_UTR_variant	2/2	ENST00000374369.8
GDF5-AS1	NR_161326.1	n.135+321A>G		intron_variant, non_coding_transcript_variant
GDF5	NM_001319138.2	c.*425T>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF5	ENST00000374369.8	c.*425T>C		3_prime_UTR_variant	2/2	1	NM_000557.5	P1
GDF5	ENST00000374372.1	c.*425T>C		3_prime_UTR_variant	4/4	1		P1
GDF5-AS1	ENST00000374375.1	n.135+321A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8601 AN: 152142 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0526

Gnomad OTH AF: 0.0559

GnomAD4 exome AF: 0.0867 AC: 16148 AN: 186330 Hom.: 1193 Cov.: 0 AF XY: 0.100 AC XY: 10136 AN XY: 101282

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.0758

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.0643

Gnomad4 NFE exome AF: 0.0529

Gnomad4 OTH exome AF: 0.0670

GnomAD4 genome AF: 0.0566 AC: 8619 AN: 152260 Hom.: 369 Cov.: 32 AF XY: 0.0596 AC XY: 4435 AN XY: 74428

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.0383

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.0526

Gnomad4 OTH AF: 0.0638

Alfa AF: 0.0493 Hom.: 67

Bravo AF: 0.0500

Asia WGS AF: 0.241 AC: 838 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Grebe syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Multiple synostoses syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

This variant is associated with the following publications: (PMID: 19565498) -

Brachydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Acromesomelic dysplasia 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Acromesomelic dysplasia 2C, Hunter-Thompson type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.4
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs56366915; hg19: chr20-34021282;