rs387906945

Variant names:

• chr12-7690059-A-C
• rs387906945
• NM_020634.3:c.914T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-7690059-A-C
• chr12-7690059-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_020634.3(GDF3):​c.914T>G​(p.Leu305Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L305P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.38
• Publications: 4 publications found

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: G2P, Labcorp Genetics (formerly Invitae)
• microphthalmia, isolated, with coloboma 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 12-7690059-A-C is Pathogenic according to our data. Variant chr12-7690059-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 423808.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF3	NM_020634.3	c.914T>G	p.Leu305Arg	missense_variant	Exon 2 of 2	ENST00000329913.4	NP_065685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF3	ENST00000329913.4	c.914T>G	p.Leu305Arg	missense_variant	Exon 2 of 2	1	NM_020634.3	ENSP00000331745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 23, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L305R variant in the GDF3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L305R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L305R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L305R as a strong candidate for a pathogenic variant; however, the possibility it is may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.88		Gain of disorder (P = 0.0258);
MVP		0.96
MPC		0.65
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.88
gMVP		0.87
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906945; hg19: chr12-7842655;