Genetic Variant GDF5:c.*193G>T (chr20-35433716-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000557.5(GDF5):c.*193G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 659,324 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 110 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 48 hom. )

Consequence

GDF5
NM_000557.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.186

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-35433716-C-A is Benign according to our data. Variant chr20-35433716-C-A is described in ClinVar as Benign. ClinVar VariationId is 338314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

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.*193G>T	3_prime_UTR	Exon 2 of 2	NP_000548.2	P43026
GDF5	NM_001319138.2		c.*193G>T	3_prime_UTR	Exon 4 of 4	NP_001306067.1	P43026
GDF5-AS1	NR_161326.1		n.136-136C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF5	ENST00000374369.8	TSL:1 MANE Select	c.*193G>T	3_prime_UTR	Exon 2 of 2	ENSP00000363489.3	P43026
GDF5	ENST00000374372.1	TSL:1	c.*193G>T	3_prime_UTR	Exon 4 of 4	ENSP00000363492.1	P43026
GDF5	ENST00000968510.1		c.*193G>T	3_prime_UTR	Exon 3 of 3	ENSP00000638569.1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

3005

AN:

152178

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

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:

0.000206

Gnomad OTH

AF:

0.0172

GnomAD4 exome

AF:

0.00280

AC:

1419

AN:

507028

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

614

AN XY:

272164

show subpopulations

African (AFR)

AF:

0.0673

AC:

1012

AN:

15038

American (AMR)

AF:

0.00560

AC:

177

AN:

31592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16830

East Asian (EAS)

AF:

0.00

AC:

AN:

31062

South Asian (SAS)

AF:

0.000110

AC:

AN:

54726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30794

Middle Eastern (MID)

AF:

0.00311

AC:

AN:

2254

European-Non Finnish (NFE)

AF:

0.0000777

AC:

AN:

296200

Other (OTH)

AF:

0.00680

AC:

194

AN:

28532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0198

AC:

3017

AN:

152296

Hom.:

110

Cov.:

AF XY:

0.0188

AC XY:

1402

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0682

AC:

2832

AN:

41536

American (AMR)

AF:

0.00882

AC:

135

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68030

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

138

276

415

553

691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00929

Hom.:

Bravo

AF:

0.0232

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

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)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.8

(source)

DANN

Benign

0.77

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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