chr3-30627192-A-G

Variant names:

• chr3-30627192-A-G
• rs4522809
• NM_003242.6:c.95-17555A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003242.6(TGFBR2):​c.95-17555A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 151,966 control chromosomes in the GnomAD database, including 17,232 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17232 hom., cov: 31)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389
• Publications: 37 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.95-17555A>G		intron	N/A	NP_003233.4
	TGFBR2	NM_001407126.1		c.169+3919A>G		intron	N/A	NP_001394055.1
	TGFBR2	NM_001407127.1		c.95-17555A>G		intron	N/A	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.95-17555A>G		intron	N/A	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.169+3919A>G		intron	N/A	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.67+3919A>G		intron	N/A	ENSP00000519658.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72128 AN: 151850 Hom.: 17228 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.481

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.475 AC: 72176 AN: 151966 Hom.: 17232 Cov.: 31 AF XY: 0.474 AC XY: 35223 AN XY: 74266

African (AFR) AF: 0.500 AC: 20723 AN: 41430

American (AMR) AF: 0.500 AC: 7629 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3464

East Asian (EAS) AF: 0.292 AC: 1503 AN: 5156

South Asian (SAS) AF: 0.446 AC: 2152 AN: 4824

European-Finnish (FIN) AF: 0.450 AC: 4749 AN: 10548

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31749 AN: 67966

Other (OTH) AF: 0.482 AC: 1016 AN: 2108

Alfa AF: 0.470 Hom.: 72336

Bravo AF: 0.481

Asia WGS AF: 0.369 AC: 1283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs4522809; hg19: chr3-30668684;