3-30650379-GAA-GAAA

Position:

• chr3-30650379-GAA-GAAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_003242.6(TGFBR2):​c.383dupA​(p.Pro129fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,515,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 7.79

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.383dupA	p.Pro129fs	frameshift_variant	3/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.383dupA	p.Pro129fs	frameshift_variant	3/7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.458dupA	p.Pro154fs	frameshift_variant	4/8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.1979dupA		non_coding_transcript_exon_variant	3/7
TGFBR2	ENST00000673250.1	n.507dupA		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 146808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000141 AC: 193 AN: 1368928 Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 87 AN XY: 682758

Gnomad4 AFR exome AF: 0.000226

Gnomad4 AMR exome AF: 0.0000475

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000540

Gnomad4 SAS exome AF: 0.0000486

Gnomad4 FIN exome AF: 0.000140

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.000159

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 146808 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000302

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change creates a premature translational stop signal (p.Pro129Alafs*3) in the TGFBR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TGFBR2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of TGFBR2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 662321). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This variant causes duplication of a nucleotide in exon 3 of the TGFBR2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TGFBR2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2022

The c.383dupA (p.Pro129fs) variant in TGFBR2 has not been previously reported in individuals with Loeys-Dietz Syndrome. This variant has been identified in 50/74078 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756007977), though the ability of these studies to accurately detect indels may be limited, as this variant occurs within a sequence of A repeats. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 129 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While loss of function variants in TGFBR2 have been reported in Loeys-Dietz syndrome, the location of this variant in a sequence of mononucleotide repeats, as well as the prevalence of this variant in population databases and absence in affected individuals provides conflicting evidence of pathogenicity. In summary, the clinical significance of the p.Pro129fs variant is uncertain. -

Loeys-Dietz syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79375991; hg19: chr3-30691871;