3-30688482-G-T

Variant names:

• chr3-30688482-G-T
• rs397516840
• NM_003242.6:c.1495G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003242.6(TGFBR2):​c.1495G>T​(p.Glu499*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86
• Publications: 5 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-30688482-G-T is Pathogenic according to our data. Variant chr3-30688482-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 44657.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.1495G>T	p.Glu499*	stop_gained	Exon 6 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1678G>T	p.Glu560*	stop_gained	Exon 8 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1603G>T	p.Glu535*	stop_gained	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.1495G>T	p.Glu499*	stop_gained	Exon 6 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.1570G>T	p.Glu524*	stop_gained	Exon 7 of 8	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.1468G>T	p.Glu490*	stop_gained	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome Pathogenic:1

Apr 09, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu499X variant (TGFBR2) has not been reported in the literature nor previou sly identified by our laboratory. This nonsense variant is located within the se rine-threonine kinase domain and leads to a premature termination codon at posit ion 499, which is predicted to lead to a truncated or absent protein. Two nonsen se variants in TGFBR2 in close proximity to this variant have been previously re ported as pathogenic (Arg495X and Arg497X). The Arg495X variant was reported in an individual with Loeys-Dietz syndrome and a histological assessment of the ind ividual?s aortic tissue supported increased TGF-beta signaling (Loeys 2006). The Arg497X variant was reported in an individual with dilated ascending aorta with out dissection and skeletal system involvement (Singh 2006). In summary, this va riant is likely to be pathogenic, though segregation studies and functional anal yses are required to fully establish the pathogenicity of this variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.9
Vest4		0.94
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs397516840; hg19: chr3-30729974; COSMIC: COSV55457199;