rs1553630282

Variant names:

• chr3-30672317-GGACCTC-G
• rs1553630282
• NM_003242.6:c.1135_1140delGACCTC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_001407126.1(TGFBR2):​c.1318_1323delGACCTC​(p.Asp440_Leu441del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D440D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_001407126.1 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_001407126.1
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001407126.1.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407126.1. 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.1135_1140delGACCTC	p.Asp379_Leu380del	conservative_inframe_deletion	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1318_1323delGACCTC	p.Asp440_Leu441del	conservative_inframe_deletion	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1243_1248delGACCTC	p.Asp415_Leu416del	conservative_inframe_deletion	Exon 5 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.1135_1140delGACCTC	p.Asp379_Leu380del	conservative_inframe_deletion	Exon 4 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.1210_1215delGACCTC	p.Asp404_Leu405del	conservative_inframe_deletion	Exon 5 of 8	ENSP00000351905.4
	TGFBR2	ENST00000941789.1		c.1135_1140delGACCTC	p.Asp379_Leu380del	conservative_inframe_deletion	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs1553630282; hg19: chr3-30713809;