12-7690390-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_020634.3(GDF3):c.583C>T(p.Arg195Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,998 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: GDF3 NM_020634.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.175

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 -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-7690389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30593.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010171175).
• BP6: Variant 12-7690390-G-A is Benign according to our data. Variant chr12-7690390-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 767184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-7690390-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 233 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF3	NM_020634.3	c.583C>T	p.Arg195Trp	missense_variant	2/2	ENST00000329913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF3	ENST00000329913.4	c.583C>T	p.Arg195Trp	missense_variant	2/2	1	NM_020634.3	P1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000465 AC: 117 AN: 251478 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135914

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000215 AC: 315 AN: 1461820 Hom.: 1 Cov.: 34 AF XY: 0.000223 AC XY: 162 AN XY: 727236

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152178 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74404

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.00173

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GDF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Klippel-Feil syndrome 3, autosomal dominant;C3150968:Microphthalmia, isolated, with coloboma 6;C3150969:Isolated microphthalmia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Klippel-Feil syndrome 3, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	9.5
Dann	Benign	0.90
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Benign	0.065	T
Sift4G	Benign	0.087	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.47
MPC		0.11
ClinPred		0.0055	T
GERP RS		-0.91
Varity_R		0.037
gMVP		0.30

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: rs112895783; hg19: chr12-7842986; COSMIC: COSV61713545;