Variant chr12-7689991-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020634.3(GDF3):c.982G>C(p.Val328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,613,794 control chromosomes in the GnomAD database, including 1,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 61 hom., cov: 32)

Exomes 𝑓: 0.032 ( 980 hom. )

Consequence

GDF3
NM_020634.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.12

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075102746).

BP6

Variant 12-7689991-C-G is Benign according to our data. Variant chr12-7689991-C-G is described in ClinVar as [Benign]. Clinvar id is 471501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7689991-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF3	NM_020634.3 link	c.982G>C	p.Val328Leu	missense_variant	2/2	ENST00000329913.4	NP_065685.1	Q9NR23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF3	ENST00000329913.4 link	c.982G>C	p.Val328Leu	missense_variant	2/2	1	NM_020634.3	ENSP00000331745.3		Q9NR23

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3492

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0478

Gnomad SAS

AF:

0.0736

Gnomad FIN

AF:

0.0393

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0296

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.0312

AC:

7852

AN:

251474

Hom.:

217

AF XY:

0.0339

AC XY:

4603

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.00729

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0388

Gnomad SAS exome

AF:

0.0660

Gnomad FIN exome

AF:

0.0398

Gnomad NFE exome

AF:

0.0326

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0318

AC:

46427

AN:

1461576

Hom.:

980

Cov.:

AF XY:

0.0327

AC XY:

23756

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.00769

Gnomad4 ASJ exome

AF:

0.00574

Gnomad4 EAS exome

AF:

0.0506

Gnomad4 SAS exome

AF:

0.0624

Gnomad4 FIN exome

AF:

0.0393

Gnomad4 NFE exome

AF:

0.0312

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0229

AC:

3491

AN:

152218

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1806

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00467

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.0475

Gnomad4 SAS

AF:

0.0736

Gnomad4 FIN

AF:

0.0393

Gnomad4 NFE

AF:

0.0297

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0269

Hom.:

Bravo

AF:

0.0184

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0336

AC:

4075

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Klippel-Feil syndrome 3, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.0096

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.65

REVEL

Uncertain

0.33

Sift

Uncertain

0.018

Sift4G

Uncertain

0.019

Polyphen

0.79

Vest4

0.25

MutPred

0.29

Loss of ubiquitination at K333 (P = 0.1231);

MPC

0.14

ClinPred

0.032

GERP RS

2.3

Varity_R

0.095

gMVP

0.94

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