rs876688

Variant names:

• chr3-30684284-G-A
• rs876688
• NM_003242.6:c.1397-4100G>A

Variant summary

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

The NM_003242.6(TGFBR2):​c.1397-4100G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 151,778 control chromosomes in the GnomAD database, including 10,912 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 0.37 (10912 hom., cov: 31)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.822
• Publications: 20 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.437 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.1397-4100G>A		intron	N/A	NP_003233.4
	TGFBR2	NM_001407126.1		c.1580-4100G>A		intron	N/A	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1505-4100G>A		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.1397-4100G>A		intron	N/A	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1472-4100G>A		intron	N/A	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.1397-4070G>A		intron	N/A	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56706 AN: 151662 Hom.: 10890 Cov.: 31

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.374 AC: 56777 AN: 151778 Hom.: 10912 Cov.: 31 AF XY: 0.376 AC XY: 27879 AN XY: 74144

African (AFR) AF: 0.402 AC: 16617 AN: 41366

American (AMR) AF: 0.446 AC: 6812 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1225 AN: 5168

South Asian (SAS) AF: 0.198 AC: 954 AN: 4814

European-Finnish (FIN) AF: 0.451 AC: 4735 AN: 10496

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24524 AN: 67882

Other (OTH) AF: 0.327 AC: 692 AN: 2116

Alfa AF: 0.363 Hom.: 30376

Bravo AF: 0.380

Asia WGS AF: 0.236 AC: 818 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.34
DANN	Benign	0.16
PhyloP100		-0.82
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: rs876688; hg19: chr3-30725776;