12-7689945-T-C

Position:

• chr12-7689945-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020634.3(GDF3):​c.1028A>G​(p.Asp343Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF3	NM_020634.3	c.1028A>G	p.Asp343Gly	missense_variant	2/2	ENST00000329913.4	NP_065685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF3	ENST00000329913.4	c.1028A>G	p.Asp343Gly	missense_variant	2/2	1	NM_020634.3	ENSP00000331745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.1028A>G (p.D343G) alteration is located in exon 2 (coding exon 2) of the GDF3 gene. This alteration results from a A to G substitution at nucleotide position 1028, causing the aspartic acid (D) at amino acid position 343 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.91		Loss of stability (P = 0.0146);
MVP		0.94
MPC		0.62
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7842541;