20-35433389-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS1

The NM_000557.5(GDF5):c.*520T>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 0.00123 in 311,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

GDF5
NM_000557.5 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, single submitter B:5

Conservation

PhyloP100: -0.0320

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 20-35433389-A-G is Benign according to our data. Variant chr20-35433389-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338309.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00218 (332/152272) while in subpopulation AFR AF = 0.00758 (315/41546). AF 95% confidence interval is 0.00689. There are 0 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000557.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF5	NM_000557.5	MANE Select	c.*520T>C	3_prime_UTR	Exon 2 of 2	NP_000548.2	P43026
GDF5	NM_001319138.2		c.*520T>C	3_prime_UTR	Exon 4 of 4	NP_001306067.1	P43026
GDF5-AS1	NR_161326.1		n.135+226A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF5	ENST00000374369.8	TSL:1 MANE Select	c.*520T>C	3_prime_UTR	Exon 2 of 2	ENSP00000363489.3	P43026
GDF5	ENST00000374372.1	TSL:1	c.*520T>C	3_prime_UTR	Exon 4 of 4	ENSP00000363492.1	P43026
GDF5	ENST00000968510.1		c.*520T>C	3_prime_UTR	Exon 3 of 3	ENSP00000638569.1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00760

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000314

AC:

AN:

159130

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

86600

show subpopulations

African (AFR)

AF:

0.00872

AC:

AN:

4358

American (AMR)

AF:

0.000766

AC:

AN:

7828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3654

East Asian (EAS)

AF:

0.00

AC:

AN:

6562

South Asian (SAS)

AF:

0.00

AC:

AN:

31412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

550

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

89598

Other (OTH)

AF:

0.000633

AC:

AN:

7898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152272

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00758

AC:

315

AN:

41546

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000840

Hom.:

Bravo

AF:

0.00235

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Acromesomelic dysplasia 2B (1)

Acromesomelic dysplasia 2C, Hunter-Thompson type (1)

Brachydactyly (1)

Grebe syndrome (1)

Multiple synostoses syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.5

(source)

DANN

Benign

0.64

PhyloP100

-0.032

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over