12-7690336-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020634.3(GDF3):c.637G>A(p.Gly213Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,536 control chromosomes in the GnomAD database, including 72,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5120 hom., cov: 31)
  • Exomes 𝑓: 0.30 (67854 hom.)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.441

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005533129).
• BP6: Variant 12-7690336-C-T is Benign according to our data. Variant chr12-7690336-C-T is described in ClinVar as [Benign]. Clinvar id is 1164810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7690336-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF3	NM_020634.3	c.637G>A	p.Gly213Arg	missense_variant	2/2	ENST00000329913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF3	ENST00000329913.4	c.637G>A	p.Gly213Arg	missense_variant	2/2	1	NM_020634.3	P1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38501 AN: 151858 Hom.: 5113 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.261 AC: 65535 AN: 251458 Hom.: 9257 AF XY: 0.272 AC XY: 36922 AN XY: 135906

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.300 AC: 438995 AN: 1461558 Hom.: 67854 Cov.: 35 AF XY: 0.302 AC XY: 219579 AN XY: 727108

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.280

GnomAD4 genome AF: 0.254 AC: 38531 AN: 151978 Hom.: 5120 Cov.: 31 AF XY: 0.253 AC XY: 18782 AN XY: 74282

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.237

Alfa AF: 0.286 Hom.: 8700

Bravo AF: 0.241

TwinsUK AF: 0.308 AC: 1142

ALSPAC AF: 0.320 AC: 1232

ESP6500AA AF: 0.185 AC: 813

ESP6500EA AF: 0.309 AC: 2656

ExAC AF: 0.264 AC: 32067

Asia WGS AF: 0.209 AC: 726 AN: 3478

EpiCase AF: 0.305

EpiControl AF: 0.299

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

Nov 12, 2018

- -

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	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.4
Dann	Benign	0.83
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.022
Sift	Benign	0.32	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.032
MutPred		0.14		Gain of phosphorylation at S212 (P = 0.1036);
MPC		0.14
ClinPred		0.0033	T
GERP RS		1.6
Varity_R		0.073
gMVP		0.28

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: rs12819884; hg19: chr12-7842932; COSMIC: COSV61712010;