rs114550865

Positions:

chr20-35437541-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000557.5(GDF5):c.388G>A(p.Gly130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,614,144 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

GDF5
NM_000557.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.27

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006139487).

BP6

Variant 20-35437541-C-T is Benign according to our data. Variant chr20-35437541-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00239 (364/152266) while in subpopulation AFR AF= 0.00823 (342/41540). AF 95% confidence interval is 0.00751. There are 1 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF5	NM_000557.5 linkuse as main transcript	c.388G>A	p.Gly130Arg	missense_variant	1/2	ENST00000374369.8	NP_000548.2	P43026F1T0J1
GDF5	NM_001319138.2 linkuse as main transcript	c.388G>A	p.Gly130Arg	missense_variant	3/4		NP_001306067.1	P43026F1T0J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8 linkuse as main transcript	c.388G>A	p.Gly130Arg	missense_variant	1/2	1	NM_000557.5	ENSP00000363489.3		P43026
GDF5	ENST00000374372.1 linkuse as main transcript	c.388G>A	p.Gly130Arg	missense_variant	3/4	1		ENSP00000363492.1		P43026

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00826

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000132

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000661

AC:

166

AN:

251030

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00843

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000314

AC:

459

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

205

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00875

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000971

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.00239

AC:

364

AN:

152266

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00823

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.00249

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000857

AC:

104

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.60

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.16

Sift

Benign

0.076

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.0020

B;B

Vest4

0.23

MutPred

0.38

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.66

MPC

0.27

ClinPred

0.024

GERP RS

3.4

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over