20-35433484-A-G

Variant names:

• chr20-35433484-A-G
• rs56366915
• NM_000557.5:c.*425T>C

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.*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:7
• Conservation: PhyloP100: 0.243
• Publications: 10 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 (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 VariationId 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 rank	MANE	Protein	UniProt
GDF5	NM_000557.5	c.*425T>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000374369.8	NP_000548.2
GDF5	NM_001319138.2	c.*425T>C		3_prime_UTR_variant	Exon 4 of 4		NP_001306067.1
GDF5-AS1	NR_161326.1	n.135+321A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8	c.*425T>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_000557.5	ENSP00000363489.3
GDF5	ENST00000374372.1	c.*425T>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000363492.1
GDF5-AS1	ENST00000374375.1	n.135+321A>G		intron_variant	Intron 1 of 1	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

African (AFR) AF: 0.0328 AC: 169 AN: 5148

American (AMR) AF: 0.0311 AC: 295 AN: 9486

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 335 AN: 4422

East Asian (EAS) AF: 0.173 AC: 1340 AN: 7734

South Asian (SAS) AF: 0.200 AC: 7256 AN: 36228

European-Finnish (FIN) AF: 0.0643 AC: 550 AN: 8548

Middle Eastern (MID) AF: 0.0625 AC: 40 AN: 640

European-Non Finnish (NFE) AF: 0.0529 AC: 5554 AN: 105032

Other (OTH) AF: 0.0670 AC: 609 AN: 9092

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

African (AFR) AF: 0.0354 AC: 1472 AN: 41562

American (AMR) AF: 0.0383 AC: 585 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3468

East Asian (EAS) AF: 0.173 AC: 895 AN: 5174

South Asian (SAS) AF: 0.211 AC: 1015 AN: 4814

European-Finnish (FIN) AF: 0.0617 AC: 655 AN: 10610

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0526 AC: 3577 AN: 68018

Other (OTH) AF: 0.0638 AC: 135 AN: 2116

Alfa AF: 0.0549 Hom.: 403

Bravo AF: 0.0500

Asia WGS AF: 0.241 AC: 838 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Grebe syndrome Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Brachydactyly Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56366915; hg19: chr20-34021282;