3-30655838-C-G

Variant names:

• chr3-30655838-C-G
• rs1367610
• NM_003242.6:c.454+5378C>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.454+5378C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.909 in 152,306 control chromosomes in the GnomAD database, including 63,112 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 0.91 (63112 hom., cov: 32)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.702
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.454+5378C>G		intron	N/A	NP_003233.4
	TGFBR2	NM_001407126.1		c.529+5378C>G		intron	N/A	NP_001394055.1
	TGFBR2	NM_001407127.1		c.454+5378C>G		intron	N/A	NP_001394056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.454+5378C>G		intron	N/A	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.529+5378C>G		intron	N/A	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.454+5378C>G		intron	N/A	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138319 AN: 152188 Hom.: 63050 Cov.: 32

Gnomad AFR AF: 0.977

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.901

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

GnomAD4 genome AF: 0.909 AC: 138440 AN: 152306 Hom.: 63112 Cov.: 32 AF XY: 0.910 AC XY: 67802 AN XY: 74476

African (AFR) AF: 0.977 AC: 40613 AN: 41574

American (AMR) AF: 0.917 AC: 14023 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 3164 AN: 3470

East Asian (EAS) AF: 0.990 AC: 5125 AN: 5176

South Asian (SAS) AF: 0.908 AC: 4385 AN: 4828

European-Finnish (FIN) AF: 0.891 AC: 9453 AN: 10606

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58749 AN: 68032

Other (OTH) AF: 0.903 AC: 1908 AN: 2114

Alfa AF: 0.893 Hom.: 7536

Bravo AF: 0.915

Asia WGS AF: 0.960 AC: 3338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.34
DANN	Benign	0.47
PhyloP100		-0.70
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: rs1367610; hg19: chr3-30697330;