Genetic Variant GDF5:c.-275delC (chr20-35438202-CG-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000557.5(GDF5):c.-275delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 381,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

GDF5
NM_000557.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

0 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 Gene-Disease associations (from GenCC):

brachydactyly type C
Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
symphalangism, proximal, 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
acromesomelic dysplasia 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
brachydactyly type A1C
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Angel-shaped phalango-epiphyseal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
brachydactyly type A1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
brachydactyly type A2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple synostoses syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
proximal symphalangism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acromesomelic dysplasia 2B
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
acromesomelic dysplasia 2C, Hunter-Thompson type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GDF5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF5	NM_000557.5 link	c.-275delC		5_prime_UTR_variant	Exon 1 of 2	ENST00000374369.8	NP_000548.2	P43026F1T0J1
GDF5	NM_001319138.2 link	c.-241-34delC		intron_variant	Intron 2 of 3		NP_001306067.1	P43026F1T0J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF5	ENST00000374369.8 link	c.-275delC		5_prime_UTR_variant	Exon 1 of 2	1	NM_000557.5	ENSP00000363489.3		P43026
GDF5	ENST00000374372.1 link	c.-241-34delC		intron_variant	Intron 2 of 3	1		ENSP00000363492.1		P43026

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000262

AC:

AN:

381844

Hom.:

Cov.:

AF XY:

0.00000496

AC XY:

AN XY:

201616

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

10890

American (AMR)

AF:

0.00

AC:

AN:

16728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11790

East Asian (EAS)

AF:

0.00

AC:

AN:

25426

South Asian (SAS)

AF:

0.0000237

AC:

AN:

42130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

228088

Other (OTH)

AF:

0.00

AC:

AN:

22192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over