chr12-7690015-C-A

Variant names:

• chr12-7690015-C-A
• rs755496462
• NM_020634.3:c.958G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020634.3(GDF3):​c.958G>T​(p.Val320Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31835786).

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.958G>T	p.Val320Phe	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.958G>T	p.Val320Phe	missense	Exon 2 of 2	ENSP00000331745.3	Q9NR23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.10
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.042	B
Vest4		0.21
MutPred		0.67		Gain of relative solvent accessibility (P = 0.281)
MVP		0.84
MPC		0.49
ClinPred		0.36	T
GERP RS		1.4
Varity_R		0.14
gMVP		0.91
Mutation Taster		=100/0	polymorphism

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: rs755496462; hg19: chr12-7842611;