3-30650379-GAA-GAAA

Variant names:

• chr3-30650379-G-GA
• rs79375991
• NM_003242.6:c.383dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_003242.6(TGFBR2):​c.383dupA​(p.Pro129AlafsTer3) 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K128K) has been classified as Likely benign. 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
• Publications: 23 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.383dupA	p.Pro129AlafsTer3	frameshift	Exon 3 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.458dupA	p.Pro154AlafsTer3	frameshift	Exon 4 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.383dupA	p.Pro129AlafsTer3	frameshift	Exon 3 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.383dupA	p.Pro129AlafsTer3	frameshift	Exon 3 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.458dupA	p.Pro154AlafsTer3	frameshift	Exon 4 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.383dupA	p.Pro129AlafsTer3	frameshift	Exon 3 of 7	ENSP00000611848.1

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

GnomAD2 exomes AF: 0.000349 AC: 58 AN: 166250 AF XY: 0.000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000864

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0000641

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000226 AC: 7 AN: 31020

American (AMR) AF: 0.0000475 AC: 2 AN: 42098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24500

East Asian (EAS) AF: 0.0000540 AC: 2 AN: 37042

South Asian (SAS) AF: 0.0000486 AC: 4 AN: 82226

European-Finnish (FIN) AF: 0.000140 AC: 7 AN: 49860

Middle Eastern (MID) AF: 0.000367 AC: 2 AN: 5452

European-Non Finnish (NFE) AF: 0.000154 AC: 160 AN: 1040294

Other (OTH) AF: 0.000159 AC: 9 AN: 56436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 39954

American (AMR) AF: 0.0000680 AC: 1 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000302 AC: 2 AN: 66330

Other (OTH) AF: 0.00 AC: 0 AN: 1986

Alfa AF: 0.000949 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=2/198	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs79375991; hg19: chr3-30691871; COSMIC: COSV55442537;