Variant 12-7690336-C-T 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.637G>A(p.Gly213Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,536 control chromosomes in the GnomAD database, including 72,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.25 ( 5120 hom., cov: 31)

Exomes 𝑓: 0.30 ( 67854 hom. )

Consequence

GDF3
NM_020634.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.441

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005533129).

BP6

Variant 12-7690336-C-T is Benign according to our data. Variant chr12-7690336-C-T is described in ClinVar as [Benign]. Clinvar id is 1164810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7690336-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF3	NM_020634.3 link	c.637G>A	p.Gly213Arg	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.637G>A	p.Gly213Arg	missense_variant	2/2	1	NM_020634.3	ENSP00000331745.3		Q9NR23

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38501

AN:

151858

Hom.:

5113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.239

GnomAD3 exomes

AF:

0.261

AC:

65535

AN:

251458

Hom.:

9257

AF XY:

0.272

AC XY:

36922

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.151

Gnomad SAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.294

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.300

AC:

438995

AN:

1461558

Hom.:

67854

Cov.:

AF XY:

0.302

AC XY:

219579

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.134

Gnomad4 ASJ exome

AF:

0.263

Gnomad4 EAS exome

AF:

0.149

Gnomad4 SAS exome

AF:

0.325

Gnomad4 FIN exome

AF:

0.291

Gnomad4 NFE exome

AF:

0.317

Gnomad4 OTH exome

AF:

0.280

GnomAD4 genome

AF:

0.254

AC:

38531

AN:

151978

Hom.:

5120

Cov.:

AF XY:

0.253

AC XY:

18782

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.280

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.299

Gnomad4 NFE

AF:

0.308

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.286

Hom.:

8700

Bravo

AF:

0.241

TwinsUK

AF:

0.308

AC:

1142

ALSPAC

AF:

0.320

AC:

1232

ESP6500AA

AF:

0.185

AC:

813

ESP6500EA

AF:

0.309

AC:

2656

ExAC

AF:

0.264

AC:

32067

Asia WGS

AF:

0.209

AC:

726

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.299

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Klippel-Feil syndrome 3, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.4

DANN

Benign

0.83

DEOGEN2

Benign

0.21

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

REVEL

Benign

0.022

Sift

Benign

0.32

Sift4G

Benign

0.61

Polyphen

0.0010

Vest4

0.032

MutPred

0.14

Gain of phosphorylation at S212 (P = 0.1036);

MPC

0.14

ClinPred

0.0033

GERP RS

1.6

Varity_R

0.073

gMVP

0.28

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