rs121918715

Variant names:

• chr3-30688511-G-A
• rs121918715
• NM_003242.6:c.1524G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-30688511-G-A
• chr3-30688511-G-C
• chr3-30688511-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003242.6(TGFBR2):​c.1524G>A​(p.Gln508Gln) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9768
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.02
• Publications: 6 publications found

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

TGFBR2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-30688511-G-A is Pathogenic according to our data. Variant chr3-30688511-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12504.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003242.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.1524G>A	p.Gln508Gln	splice_region synonymous	Exon 6 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1707G>A	p.Gln569Gln	splice_region synonymous	Exon 8 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1632G>A	p.Gln544Gln	splice_region synonymous	Exon 7 of 8	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.1524G>A	p.Gln508Gln	splice_region synonymous	Exon 6 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.1599G>A	p.Gln533Gln	splice_region synonymous	Exon 7 of 8	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.1497G>A	p.Gln499Gln	splice_region synonymous	Exon 7 of 8	ENSP00000519658.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 2 Pathogenic:2

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 01, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR2 NM_001024847.2 exon7 p.Gln533Gln (c.1599G>A): This variant has been reported in the literature in 1 individual with clinical suspicion of Marfan/Loeys-Dietz syndrome (reported as Marfan Syndrome type 2), segregating with disease in 11 affected family members (reported as p.Gln508Gln, Mizguchi 2004 PMID:15235604). This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant is "silent" and is not predicted to alter the amino acid, functional studies have indicated that this variant affects splicing (Mizguchi 2004 PMID:15235604). In summary, this variant is classified as pathogenic based on the data above (segregation studies, absence from controls, predicted impact to protein).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Benign	0.93
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 23
DS_DL_spliceai		0.39		Position offset: 0

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

Other links and lift over

dbSNP: rs121918715; hg19: chr3-30730003; COSMIC: COSV107343412;