chr12-7690177-G-A

Position:

chr12-7690177-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020634.3(GDF3):c.796C>T(p.Arg266Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,130 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 10 hom. )

Consequence

GDF3
NM_020634.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1B:3

Conservation

PhyloP100: 2.42

Variant links:

Genes affected

GDF3 (HGNC:4218): (growth differentiation factor 3) 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 plays a role ocular and skeletal development. Mutations in this gene are associated with microphthalmia, coloboma, and skeletal abnormalities in human patients. [provided by RefSeq, Aug 2016]

GDF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01652208).

BS2

High AC in GnomAd4 at 274 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF3	NM_020634.3 linkuse as main transcript	c.796C>T	p.Arg266Cys	missense_variant	2/2	ENST00000329913.4	NP_065685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF3	ENST00000329913.4 linkuse as main transcript	c.796C>T	p.Arg266Cys	missense_variant	2/2	1	NM_020634.3	ENSP00000331745	P1

Frequencies

GnomAD3 genomes

AF:

0.00180

AC:

274

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00196

AC:

494

AN:

251474

Hom.:

AF XY:

0.00184

AC XY:

250

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00605

Gnomad NFE exome

AF:

0.00295

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00258

AC:

3772

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1832

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00625

Gnomad4 NFE exome

AF:

0.00297

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00180

AC:

274

AN:

152246

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.00259

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00203

AC:

246

EpiCase

AF:

0.00245

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Klippel-Feil syndrome 3, autosomal dominant

Pathogenic:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2010	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2024	Observed in patients with features of GDF3-related ocular and skeletal anomalies spectrum disorder (PMID: 19864492); Published functional studies demonstrate a damaging effect on protein maturation (PMID: 29735971); This variant is associated with the following publications: (PMID: 29260090, 30653986, 34426522, 35170016, 30665703, 24278672, 33195419, 19864492, 23307924, 28440294, 30940639, 25348728, 29735971) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -

Microphthalmia, isolated, with coloboma 6

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2010

- -

Scoliosis;C0265677:Hemivertebrae;C0345397:Supernumerary ribs;C0426816:Missing ribs

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 10, 2014

- -

GDF3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.86

M_CAP

Benign

0.026

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.67

Sift

Benign

0.031

Sift4G

Uncertain

0.051

Polyphen

0.90

Vest4

0.46

MVP

0.90

MPC

0.23

ClinPred

0.11

GERP RS

4.6

Varity_R

0.54

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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