rs3781226

Variant names:

• chr10-47323104-G-A
• rs3781226
• NM_016204.4:c.346+90G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-47323104-G-A
• chr10-47323104-G-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.346+90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 820,276 control chromosomes in the GnomAD database, including 3,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (457 hom., cov: 33)
  • Exomes 𝑓: 0.085 (2800 hom.)
• Consequence: GDF2 NM_016204.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.376
• Publications: 5 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=-0.78).
• BP6: Variant 10-47323104-G-A is Benign according to our data. Variant chr10-47323104-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF2	NM_016204.4	c.346+90G>A		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.346+90G>A		intron_variant	Intron 1 of 1	1	NM_016204.4	ENSP00000463051.1

Frequencies

GnomAD3 genomes AF: 0.0681 AC: 10371 AN: 152186 Hom.: 459 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.0979

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.0970

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0766

GnomAD4 exome AF: 0.0854 AC: 57012 AN: 667972 Hom.: 2800 AF XY: 0.0866 AC XY: 29408 AN XY: 339518

African (AFR) AF: 0.0167 AC: 291 AN: 17386

American (AMR) AF: 0.0582 AC: 1281 AN: 22026

Ashkenazi Jewish (ASJ) AF: 0.0961 AC: 1433 AN: 14906

East Asian (EAS) AF: 0.181 AC: 6200 AN: 34220

South Asian (SAS) AF: 0.0886 AC: 3647 AN: 41184

European-Finnish (FIN) AF: 0.0864 AC: 3792 AN: 43886

Middle Eastern (MID) AF: 0.149 AC: 464 AN: 3106

European-Non Finnish (NFE) AF: 0.0813 AC: 37250 AN: 458360

Other (OTH) AF: 0.0807 AC: 2654 AN: 32898

GnomAD4 genome AF: 0.0680 AC: 10362 AN: 152304 Hom.: 457 Cov.: 33 AF XY: 0.0702 AC XY: 5226 AN XY: 74462

African (AFR) AF: 0.0171 AC: 711 AN: 41562

American (AMR) AF: 0.0746 AC: 1142 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 340 AN: 3472

East Asian (EAS) AF: 0.157 AC: 815 AN: 5178

South Asian (SAS) AF: 0.0967 AC: 467 AN: 4830

European-Finnish (FIN) AF: 0.0888 AC: 942 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0837 AC: 5694 AN: 68026

Other (OTH) AF: 0.0758 AC: 160 AN: 2112

Alfa AF: 0.0795 Hom.: 312

Bravo AF: 0.0641

Asia WGS AF: 0.120 AC: 416 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

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		0.38

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

Other links and lift over

dbSNP: rs3781226; hg19: chr10-48416258;