3-30650379-GAA-GA

Variant names:

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

Variant summary

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

The NM_003242.6(TGFBR2):​c.383delA​(p.Lys128SerfsTer35) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,376,860 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 Conflicting classifications of pathogenicity (no stars). 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 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR2 NM_003242.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:6 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.383delA	p.Lys128SerfsTer35	frameshift	Exon 3 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.458delA	p.Lys153SerfsTer32	frameshift	Exon 4 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.383delA	p.Lys128SerfsTer32	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.383delA	p.Lys128SerfsTer35	frameshift	Exon 3 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.458delA	p.Lys153SerfsTer35	frameshift	Exon 4 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.383delA	p.Lys128SerfsTer35	frameshift	Exon 3 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146804 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: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00248 AC: 413 AN: 166250 AF XY: 0.00256

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.000561

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00159

Gnomad FIN exome AF: 0.000320

Gnomad NFE exome AF: 0.00340

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.000112 AC: 154 AN: 1376860 Hom.: 0 Cov.: 32 AF XY: 0.000137 AC XY: 94 AN XY: 685788

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

African (AFR) AF: 0.000161 AC: 5 AN: 31064

American (AMR) AF: 0.000288 AC: 12 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.0000817 AC: 2 AN: 24488

East Asian (EAS) AF: 0.00 AC: 0 AN: 36872

South Asian (SAS) AF: 0.000625 AC: 51 AN: 81620

European-Finnish (FIN) AF: 0.000242 AC: 12 AN: 49652

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5474

European-Non Finnish (NFE) AF: 0.0000629 AC: 66 AN: 1049208

Other (OTH) AF: 0.0000881 AC: 5 AN: 56776

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000681 AC: 1 AN: 146804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71298

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

African (AFR) AF: 0.00 AC: 0 AN: 39960

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: 0.000105 AC: 1 AN: 9514

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66322

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00242 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not specified (3)
-	1	1	not provided (2)
1	-	-	Loeys-Dietz syndrome (1)
-	1	-	Loeys-Dietz syndrome 2 (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: COSV55442522;