rs876658120

chr3-30691436-GTGAGACGTTGAC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_003242.6(TGFBR2):c.1546_1557del(p.Thr516_Glu519del) variant causes a 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C514C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003242.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-30691436-GTGAGACGTTGAC-G is Pathogenic according to our data. Variant chr3-30691436-GTGAGACGTTGAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229649.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1546_1557del	p.Thr516_Glu519del	inframe_deletion	7/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1546_1557del	p.Thr516_Glu519del	inframe_deletion	7/7	1	NM_003242.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 25, 2011

The 1546_1557del (Thr516_Glu519del) variant has not previously been reported in the literature or in public databases. This variant has been shown to have occur red de novo in one affected individual in our laboratory, suggesting that this v ariant is pathogenic. This variant is an in-frame deletion in the last exon of T GFBR2 which removes four amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658120; hg19: chr3-30732928;