rs886058297

Variant names:

• chr3-30606513-A-C
• rs886058297
• XM_047449400.1:c.412T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001407129.1(TGFBR2):​c.-92A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 256,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TGFBR2 NM_001407129.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.32
• Publications: 0 publications found

Genes affected

LOC105377015 (HGNC:):

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):

• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407129.1. 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_001407129.1		c.-92A>C		5_prime_UTR	Exon 1 of 8	NP_001394058.1
	TGFBR2	NM_001407132.1		c.-92A>C		5_prime_UTR	Exon 1 of 7	NP_001394061.1	A0AAQ5BI06
	TGFBR2	NM_003242.6	MANE Select	c.-371A>C		upstream_gene	N/A	NP_003233.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000714391.1		c.-89A>C		5_prime_UTR	Exon 1 of 8	ENSP00000519658.1	A0AAQ5BI03
	TGFBR2	ENST00000714389.1		c.-87A>C		5_prime_UTR	Exon 1 of 7	ENSP00000519656.1	A0AAQ5BI06
	TGFBR2	ENST00000714390.1		c.-92A>C		5_prime_UTR	Exon 1 of 7	ENSP00000519657.1	A0AAQ5BI06

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000260 AC: 27 AN: 104030 Hom.: 0 Cov.: 0 AF XY: 0.000263 AC XY: 13 AN XY: 49452

African (AFR) AF: 0.00 AC: 0 AN: 4592

American (AMR) AF: 0.00 AC: 0 AN: 3000

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 21 AN: 5662

East Asian (EAS) AF: 0.00 AC: 0 AN: 12620

South Asian (SAS) AF: 0.00 AC: 0 AN: 900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 640

European-Non Finnish (NFE) AF: 0.0000925 AC: 6 AN: 64862

Other (OTH) AF: 0.00 AC: 0 AN: 8146

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Diabetic retinopathy (1)
-	1	-	Loeys-Dietz syndrome (1)
-	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	-	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.68
PhyloP100		2.3
PromoterAI		0.022	Neutral

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: rs886058297; hg19: chr3-30648005;