rs7923671

Variant names:

• chr10-47324792-T-C
• rs7923671
• NM_016204.4:c.347-49T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016204.4(GDF2):​c.347-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,345,820 control chromosomes in the GnomAD database, including 561,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55947 hom., cov: 32)
  • Exomes 𝑓: 0.92 (505925 hom.)
• Consequence: GDF2 NM_016204.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.417
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• telangiectasia, hereditary hemorrhagic, type 5

  Inheritance: AD, Unknown, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-47324792-T-C is Benign according to our data. Variant chr10-47324792-T-C is described in ClinVar as Benign. ClinVar VariationId is 674697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF2	NM_016204.4	c.347-49T>C		intron_variant	Intron 1 of 1	ENST00000581492.3	NP_057288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF2	ENST00000581492.3	c.347-49T>C		intron_variant	Intron 1 of 1	1	NM_016204.4	ENSP00000463051.1

Frequencies

GnomAD3 genomes AF: 0.849 AC: 129060 AN: 152080 Hom.: 55917 Cov.: 32

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.880

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.949

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.855

GnomAD2 exomes AF: 0.891 AC: 198295 AN: 222444 AF XY: 0.898

Gnomad AFR exome AF: 0.650

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.934

Gnomad OTH exome AF: 0.915

GnomAD4 exome AF: 0.919 AC: 1097201 AN: 1193622 Hom.: 505925 Cov.: 16 AF XY: 0.920 AC XY: 554712 AN XY: 603128

African (AFR) AF: 0.656 AC: 18542 AN: 28268

American (AMR) AF: 0.872 AC: 37566 AN: 43074

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 20615 AN: 23094

East Asian (EAS) AF: 0.862 AC: 33106 AN: 38386

South Asian (SAS) AF: 0.896 AC: 69286 AN: 77306

European-Finnish (FIN) AF: 0.953 AC: 42288 AN: 44384

Middle Eastern (MID) AF: 0.919 AC: 4732 AN: 5148

European-Non Finnish (NFE) AF: 0.935 AC: 824825 AN: 882440

Other (OTH) AF: 0.897 AC: 46241 AN: 51522

GnomAD4 genome AF: 0.848 AC: 129138 AN: 152198 Hom.: 55947 Cov.: 32 AF XY: 0.851 AC XY: 63338 AN XY: 74442

African (AFR) AF: 0.658 AC: 27277 AN: 41472

American (AMR) AF: 0.880 AC: 13461 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3136 AN: 3472

East Asian (EAS) AF: 0.818 AC: 4239 AN: 5180

South Asian (SAS) AF: 0.888 AC: 4282 AN: 4822

European-Finnish (FIN) AF: 0.949 AC: 10068 AN: 10610

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63699 AN: 68020

Other (OTH) AF: 0.854 AC: 1808 AN: 2116

Alfa AF: 0.904 Hom.: 58132

Bravo AF: 0.832

Asia WGS AF: 0.844 AC: 2936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.67
PhyloP100		-0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7923671; hg19: chr10-48414570;