NM_020634.3:c.637G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

isolated anophthalmia-microphthalmia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated Klippel-Feil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microphthalmia, isolated, with coloboma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated microphthalmia 7
Inheritance: AD Classification: LIMITED Submitted by: G2P
Klippel-Feil syndrome 3, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
microphthalmia, isolated, with coloboma 6
Inheritance: AD Classification: LIMITED Submitted by: G2P

GDF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1164810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020634.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF3	NM_020634.3	MANE Select	c.637G>A	p.Gly213Arg	missense	Exon 2 of 2	NP_065685.1	Q9NR23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF3	ENST00000329913.4	TSL:1 MANE Select	c.637G>A	p.Gly213Arg	missense	Exon 2 of 2	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

GnomAD2 exomes

AF:

0.261

AC:

65535

AN:

251458

AF XY:

0.272

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 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

African (AFR)

AF:

0.173

AC:

5797

AN:

33478

American (AMR)

AF:

0.134

AC:

5993

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6882

AN:

26136

East Asian (EAS)

AF:

0.149

AC:

5935

AN:

39700

South Asian (SAS)

AF:

0.325

AC:

27992

AN:

86258

European-Finnish (FIN)

AF:

0.291

AC:

15551

AN:

53420

Middle Eastern (MID)

AF:

0.312

AC:

1800

AN:

5768

European-Non Finnish (NFE)

AF:

0.317

AC:

352139

AN:

1111684

Other (OTH)

AF:

0.280

AC:

16906

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19017

38034

57051

76068

95085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11444

22888

34332

45776

57220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.254

AC:

38531

AN:

151978

Hom.:

5120

Cov.:

AF XY:

0.253

AC XY:

18782

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.178

AC:

7396

AN:

41484

American (AMR)

AF:

0.193

AC:

2933

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

972

AN:

3470

East Asian (EAS)

AF:

0.151

AC:

780

AN:

5162

South Asian (SAS)

AF:

0.311

AC:

1493

AN:

4808

European-Finnish (FIN)

AF:

0.299

AC:

3155

AN:

10566

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.308

AC:

20950

AN:

67938

Other (OTH)

AF:

0.237

AC:

501

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1444

2887

4331

5774

7218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.282

Hom.:

18856

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Klippel-Feil syndrome 3, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.4

(source)

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

PhyloP100

0.44

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

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over