3-30688470-C-T

Variant names:

• chr3-30688470-C-T
• rs104893819
• NM_003242.6:c.1483C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1483C>T​(p.Arg495*) variant causes a stop gained change. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000918308: An increase in intracellular collagen was observed in patient fibroblasts (Barnett_2011)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R495R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.46
• Publications: 11 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 2

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 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 42 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000918308: An increase in intracellular collagen was observed in patient fibroblasts (Barnett_2011).; SCV000250967: Published functional studies suggest a damaging effect by causing intracellular accumulation of collagen type I in patient-derived cultured fibroblasts (Barnett et al., 2011); PMID: 25525159, 16928994, 18084123, 22113417, 17652900, 33059708, 34150014, 21267002, 26582918, 33084842
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-30688470-C-T is Pathogenic according to our data. Variant chr3-30688470-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.1483C>T	p.Arg495*	stop_gained	Exon 6 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1666C>T	p.Arg556*	stop_gained	Exon 8 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1591C>T	p.Arg531*	stop_gained	Exon 7 of 8	NP_001394056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.1483C>T	p.Arg495*	stop_gained	Exon 6 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1558C>T	p.Arg520*	stop_gained	Exon 7 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.1513C>T	p.Arg505*	stop_gained	Exon 6 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial thoracic aortic aneurysm and aortic dissection (2)
2	-	-	Loeys-Dietz syndrome (2)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Loeys-Dietz syndrome 2 (1)
1	-	-	Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		4.5
Vest4		0.90
GERP RS		3.5
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: rs104893819; hg19: chr3-30729962; COSMIC: COSV55443391;