10-47325491-C-T

Position:

• chr10-47325491-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3
• Conservation: PhyloP100: 0.939

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]

ACMG classification

Verdict is Benign. Variant got -7 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}.
• BS2: High AC in GnomAd4 at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF2	NM_016204.4	c.997C>T	p.Arg333Trp	missense_variant	2/2	ENST00000581492.3	NP_057288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF2	ENST00000581492.3	c.997C>T	p.Arg333Trp	missense_variant	2/2	1	NM_016204.4	ENSP00000463051.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152224 Hom.: 0 Cov.: 33

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: 82 AN: 251426 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135904

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.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79 AN XY: 727146

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.: 0 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74488

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.: 0

Bravo AF: 0.00135

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 5 Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 2013	- -
Likely benign, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	BS1 + BP2 -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 12, 2024	BS1 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2020

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	15
DANN	Benign	0.81
DEOGEN2	Uncertain	0.54	D
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.23	T
Sift4G	Benign	0.12	T
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

Other links and lift over

dbSNP: rs35129734; hg19: chr10-48413871;