NM_016204.4:c.997C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_016204.4(GDF2):c.997C>T(p.Arg333Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GDF2
NM_016204.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 0.939

Variant links:

Genes affected

GDF2 (HGNC:4217): (growth differentiation factor 2) 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 regulates cartilage and bone development, angiogenesis and differentiation of cholinergic central nervous system neurons. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia. [provided by RefSeq, Jul 2016]

GDF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23462015).

BP6

Variant 10-47325491-C-T is Benign according to our data. Variant chr10-47325491-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 88652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00114 (174/152342) while in subpopulation AFR AF= 0.00382 (159/41596). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF2	NM_016204.4 link	c.997C>T	p.Arg333Trp	missense_variant	Exon 2 of 2	ENST00000581492.3	NP_057288.1	Q9UK05B2RC63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF2	ENST00000581492.3 link	c.997C>T	p.Arg333Trp	missense_variant	Exon 2 of 2	1	NM_016204.4	ENSP00000463051.1		Q9UK05

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251426

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00114

AC:

174

AN:

152342

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.00135

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 5

Pathogenic:1Benign:2

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

BS1 + BP2 -

Sep 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Jun 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Aug 23, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with HHT, HHT-like phenotype, or PAH in published literature (Wooderchalk-Donahue et al., 2013; Zhu et al., 2019; Balachandar et al., 2022) ; however, at least one individual harbored a pathogenic variant in another HHT-related gene (Shovlin et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; One published functional studies showed reduction in mature protein levels but no change in protein activity compared to wild type, while another showed no change in circulating mature protein levels (Wooderchak-Donahue et al., 2013; Hodgson et al., 2020); This variant is associated with the following publications: (PMID: 34611981, 25620979, 32992168, 23972370, 32573726, 34904380, 31661308, 31727138) -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 21, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_noAF

Benign

-0.84

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Uncertain

0.54

LIST_S2

Benign

0.35

MetaRNN

Benign

0.23

Sift4G

Benign

0.12

Vest4

0.51

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over