12-7689991-C-G

Variant names:

• chr12-7689991-C-G
• rs2302516
• NM_020634.3:c.982G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020634.3(GDF3):​c.982G>C​(p.Val328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,613,794 control chromosomes in the GnomAD database, including 1,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 32)
  • Exomes 𝑓: 0.032 (980 hom.)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.12
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075102746).
• BP6: Variant 12-7689991-C-G is Benign according to our data. Variant chr12-7689991-C-G is described in ClinVar as Benign. ClinVar VariationId is 471501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

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.982G>C	p.Val328Leu	missense	Exon 2 of 2	NP_065685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF3	ENST00000329913.4	TSL:1 MANE Select	c.982G>C	p.Val328Leu	missense	Exon 2 of 2	ENSP00000331745.3

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3492 AN: 152100 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0478

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0312 AC: 7852 AN: 251474 AF XY: 0.0339

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00729

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0388

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0326

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0318 AC: 46427 AN: 1461576 Hom.: 980 Cov.: 32 AF XY: 0.0327 AC XY: 23756 AN XY: 727126

African (AFR) AF: 0.00370 AC: 124 AN: 33478

American (AMR) AF: 0.00769 AC: 344 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26136

East Asian (EAS) AF: 0.0506 AC: 2010 AN: 39700

South Asian (SAS) AF: 0.0624 AC: 5378 AN: 86248

European-Finnish (FIN) AF: 0.0393 AC: 2101 AN: 53420

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0312 AC: 34739 AN: 1111724

Other (OTH) AF: 0.0256 AC: 1548 AN: 60378

GnomAD4 genome AF: 0.0229 AC: 3491 AN: 152218 Hom.: 61 Cov.: 32 AF XY: 0.0243 AC XY: 1806 AN XY: 74428

African (AFR) AF: 0.00467 AC: 194 AN: 41566

American (AMR) AF: 0.0128 AC: 196 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.0475 AC: 246 AN: 5174

South Asian (SAS) AF: 0.0736 AC: 354 AN: 4808

European-Finnish (FIN) AF: 0.0393 AC: 417 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2017 AN: 68020

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.0269 Hom.: 50

Bravo AF: 0.0184

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0336 AC: 4075

Asia WGS AF: 0.0400 AC: 140 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Klippel-Feil syndrome 3, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.0096
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.019	D
Polyphen		0.79	P
Vest4		0.25
MutPred		0.29		Loss of ubiquitination at K333 (P = 0.1231)
MPC		0.14
ClinPred		0.032	T
GERP RS		2.3
Varity_R		0.095
gMVP		0.94
Mutation Taster		=100/0	polymorphism (auto)

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: rs2302516; hg19: chr12-7842587; COSMIC: COSV105211065;