rs2302516

chr12-7689991-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 13/20 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:2
• Conservation: PhyloP100: 3.12

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 Benign. Variant got -18 ACMG points.

• PM1: In a disulfide_bond (size 65) in uniprot entity GDF3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_020634.3
• 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 id is 471501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7689991-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF3	NM_020634.3	c.982G>C	p.Val328Leu	missense_variant	2/2	ENST00000329913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF3	ENST00000329913.4	c.982G>C	p.Val328Leu	missense_variant	2/2	1	NM_020634.3	P1

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

GnomAD3 exomes AF: 0.0312 AC: 7852 AN: 251474 Hom.: 217 AF XY: 0.0339 AC XY: 4603 AN XY: 135912

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 SAS exome AF: 0.0660

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

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.00769

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.0506

Gnomad4 SAS exome AF: 0.0624

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0312

Gnomad4 OTH exome AF: 0.0256

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

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.0475

Gnomad4 SAS AF: 0.0736

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0190

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Klippel-Feil syndrome 3, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.89	N
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

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

LitVar

Other links and lift over

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