chr12-7689882-C-T

Variant names:

• chr12-7689882-C-T
• rs758777639
• NM_020634.3:c.1091G>A

Variant summary

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

The NM_020634.3(GDF3):​c.1091G>A​(p.Gly364Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,444,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G364A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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=0.41410217).

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>A	p.Gly364Glu	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>A	p.Gly364Glu	missense	Exon 2 of 2	ENSP00000331745.3	Q9NR23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444784 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 2 AN XY: 719900

African (AFR) AF: 0.00 AC: 0 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1096468

Other (OTH) AF: 0.00 AC: 0 AN: 59812

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.77	P
Vest4		0.36
MutPred		0.47		Gain of solvent accessibility (P = 0.024)
MVP		0.80
MPC		0.61
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.30
gMVP		0.85
Mutation Taster		=82/18	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: rs758777639; hg19: chr12-7842478;