Genetic Variant NM_020634.3:c.1091G>C (chr12-7689882-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_020634.3(GDF3):c.1091G>C(p.Gly364Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000831 in 1,444,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

GDF3
NM_020634.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22287169).

BS2

High AC in GnomAdExome4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1091G>C	p.Gly364Ala	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.1091G>C	p.Gly364Ala	missense	Exon 2 of 2	ENSP00000331745.3	Q9NR23

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000831

AC:

AN:

1444784

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000100

AC:

AN:

1096468

Other (OTH)

AF:

0.0000167

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

M_CAP

Benign

0.015

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.66

PhyloP100

4.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.88

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.010

Vest4

0.24

MutPred

0.47

Loss of disorder (P = 0.128)

MVP

0.76

MPC

0.39

ClinPred

0.63

GERP RS

2.9

Varity_R

0.36

gMVP

0.81

Mutation Taster

=87/13

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over