3-30649419-A-G

Variant names:

• chr3-30649419-A-G
• rs1078985
• NM_003242.6:c.264-851A>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.264-851A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,054 control chromosomes in the GnomAD database, including 4,956 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 0.25 (4956 hom., cov: 32)
• Consequence: TGFBR2 NM_003242.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599
• Publications: 29 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.264-851A>G		intron_variant	Intron 2 of 6	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.264-851A>G		intron_variant	Intron 2 of 6	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37437 AN: 151936 Hom.: 4954 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.246 AC: 37471 AN: 152054 Hom.: 4956 Cov.: 32 AF XY: 0.248 AC XY: 18410 AN XY: 74314

African (AFR) AF: 0.174 AC: 7215 AN: 41474

American (AMR) AF: 0.174 AC: 2659 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3468

East Asian (EAS) AF: 0.171 AC: 884 AN: 5172

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4818

European-Finnish (FIN) AF: 0.349 AC: 3676 AN: 10548

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20178 AN: 67968

Other (OTH) AF: 0.251 AC: 528 AN: 2106

Alfa AF: 0.277 Hom.: 24275

Bravo AF: 0.226

Asia WGS AF: 0.205 AC: 711 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.0
DANN	Benign	0.52
PhyloP100		0.60
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: rs1078985; hg19: chr3-30690911;