XM_047449400.1:c.385G>T

Variant names:

• chr3-30606540-C-A
• rs886058298
• XM_047449400.1:c.385G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The XM_047449400.1(LOC105377015):​c.385G>T​(p.Gly129Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LOC105377015 XM_047449400.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 3.60
• 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):

• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295754.10. 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.-65C>A		5_prime_UTR	Exon 1 of 8	NP_001394058.1
	TGFBR2	NM_001407132.1		c.-65C>A		5_prime_UTR	Exon 1 of 7	NP_001394061.1	A0AAQ5BI06
	TGFBR2	NM_003242.6	MANE Select	c.-344C>A		upstream_gene	N/A	NP_003233.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000714391.1		c.-62C>A		5_prime_UTR	Exon 1 of 8	ENSP00000519658.1	A0AAQ5BI03
	TGFBR2	ENST00000714389.1		c.-60C>A		5_prime_UTR	Exon 1 of 7	ENSP00000519656.1	A0AAQ5BI06
	TGFBR2	ENST00000714390.1		c.-65C>A		5_prime_UTR	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: 125722 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60722

African (AFR) AF: 0.00 AC: 0 AN: 5006

American (AMR) AF: 0.00 AC: 0 AN: 3586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6222

East Asian (EAS) AF: 0.00 AC: 0 AN: 14242

South Asian (SAS) AF: 0.00 AC: 0 AN: 1080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 78998

Other (OTH) AF: 0.00 AC: 0 AN: 9376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Loeys-Dietz syndrome (1)
-	1	-	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.92
PhyloP100		3.6
PromoterAI		-0.38	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: rs886058298; hg19: chr3-30648032;