rs79375991

Variant names:

• chr3-30650379-GAA-G
• rs79375991
• NM_003242.6:c.382_383delAA

Your query was ambiguous. Multiple possible variants found:

• chr3-30650379-GAA-G
• chr3-30650379-GAA-GA
• chr3-30650379-GAA-GAAA

Variant summary

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

The NM_003242.6(TGFBR2):​c.382_383delAA​(p.Lys128AlafsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR2 NM_003242.6 frameshift
• Clinical Significance: Not reported in ClinVar
• 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.382_383delAA	p.Lys128AlafsTer3	frameshift	Exon 3 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.457_458delAA	p.Lys153AlafsTer3	frameshift	Exon 4 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.382_383delAA	p.Lys128AlafsTer3	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.382_383delAA	p.Lys128AlafsTer3	frameshift	Exon 3 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.457_458delAA	p.Lys153AlafsTer3	frameshift	Exon 4 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.382_383delAA	p.Lys128AlafsTer3	frameshift	Exon 3 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146828 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 166250 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387684 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 691472

African (AFR) AF: 0.00 AC: 0 AN: 31434

American (AMR) AF: 0.00 AC: 0 AN: 42344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24748

East Asian (EAS) AF: 0.00 AC: 0 AN: 37452

South Asian (SAS) AF: 0.00 AC: 0 AN: 82888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055758

Other (OTH) AF: 0.00 AC: 0 AN: 57216

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 146828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71310

African (AFR) AF: 0.00 AC: 0 AN: 39968

American (AMR) AF: 0.00 AC: 0 AN: 14710

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: 0.00 AC: 0 AN: 66334

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

ClinVar

Not reported in ClinVar

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)		0.020		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: COSV55443177;