Variant 12-7690063-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS2_Supporting

The NM_020634.3(GDF3):c.910T>C(p.Ser304Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GDF3
NM_020634.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.743

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF3	NM_020634.3 link	c.910T>C	p.Ser304Pro	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.910T>C	p.Ser304Pro	missense_variant	2/2	1	NM_020634.3	ENSP00000331745.3		Q9NR23

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251470

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Klippel-Feil syndrome 3, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GDF3-related conditions. This variant is present in population databases (rs774437736, ExAC 0.01%). This sequence change replaces serine with proline at codon 304 of the GDF3 protein (p.Ser304Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.71

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.59

Sift

Benign

0.28

Sift4G

Benign

0.30

Polyphen

0.098

Vest4

0.32

MutPred

0.57

Loss of catalytic residue at S304 (P = 0.0036);

MVP

0.87

MPC

0.50

ClinPred

0.66

GERP RS

3.4

Varity_R

0.39

gMVP

0.86

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