NM_001407129.1:c.-109C>T

Variant names:

• chr3-30606496-C-T
• rs1697919506
• NM_001407129.1:c.-109C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001407129.1(TGFBR2):​c.-109C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR2 NM_001407129.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0750
• Publications: 0 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

LOC105377015 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-30606496-C-T is Benign according to our data. Variant chr3-30606496-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 901331.

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.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001394058.1
	TGFBR2	NM_001407132.1		c.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001394061.1	A0AAQ5BI06
	TGFBR2	NM_001407129.1		c.-109C>T		5_prime_UTR	Exon 1 of 8	NP_001394058.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000714391.1		c.-106C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000519658.1	A0AAQ5BI03
	TGFBR2	ENST00000714389.1		c.-104C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000519656.1	A0AAQ5BI06
	TGFBR2	ENST00000714390.1		c.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000519657.1	A0AAQ5BI06

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 96256 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 45256

African (AFR) AF: 0.00 AC: 0 AN: 4400

American (AMR) AF: 0.00 AC: 0 AN: 2810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5494

East Asian (EAS) AF: 0.00 AC: 0 AN: 12116

South Asian (SAS) AF: 0.00 AC: 0 AN: 836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59812

Other (OTH) AF: 0.00 AC: 0 AN: 7726

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Diabetic retinopathy (1)
-	1	-	Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.3
DANN	Benign	0.65
PhyloP100		0.075
PromoterAI		-0.22	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1697919506; hg19: chr3-30647988;