3-30691909-TTATATATATA-TTATATATA

Variant names:

• chr3-30691909-TTA-T
• rs4016180
• NM_003242.6:c.*328_*329delAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003242.6(TGFBR2):​c.*328_*329delAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 241,958 control chromosomes in the GnomAD database, including 9,907 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7544 hom., cov: 0)
  • Exomes 𝑓: 0.24 (2363 hom.)
• Consequence: TGFBR2 NM_003242.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 3-30691909-TTA-T is Benign according to our data. Variant chr3-30691909-TTA-T is described in ClinVar as Benign. ClinVar VariationId is 1183809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.354 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.*328_*329delAT		3_prime_UTR	Exon 7 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.*328_*329delAT		3_prime_UTR	Exon 9 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.*328_*329delAT		3_prime_UTR	Exon 8 of 8	NP_001394056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.*328_*329delAT		3_prime_UTR	Exon 7 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.*328_*329delAT		3_prime_UTR	Exon 8 of 8	ENSP00000351905.4
	TGFBR2	ENST00000941789.1		c.*328_*329delAT		3_prime_UTR	Exon 7 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 46763 AN: 147144 Hom.: 7543 Cov.: 0

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.241 AC: 22804 AN: 94778 Hom.: 2363 AF XY: 0.235 AC XY: 11068 AN XY: 47058

African (AFR) AF: 0.183 AC: 724 AN: 3958

American (AMR) AF: 0.226 AC: 1155 AN: 5110

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 1023 AN: 4268

East Asian (EAS) AF: 0.129 AC: 1393 AN: 10782

South Asian (SAS) AF: 0.129 AC: 867 AN: 6706

European-Finnish (FIN) AF: 0.209 AC: 338 AN: 1614

Middle Eastern (MID) AF: 0.188 AC: 87 AN: 464

European-Non Finnish (NFE) AF: 0.279 AC: 15398 AN: 55260

Other (OTH) AF: 0.275 AC: 1819 AN: 6616

GnomAD4 genome AF: 0.318 AC: 46768 AN: 147180 Hom.: 7544 Cov.: 0 AF XY: 0.321 AC XY: 22990 AN XY: 71630

African (AFR) AF: 0.273 AC: 10895 AN: 39868

American (AMR) AF: 0.294 AC: 4334 AN: 14740

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 832 AN: 3420

East Asian (EAS) AF: 0.114 AC: 579 AN: 5074

South Asian (SAS) AF: 0.262 AC: 1229 AN: 4684

European-Finnish (FIN) AF: 0.447 AC: 4163 AN: 9318

Middle Eastern (MID) AF: 0.264 AC: 74 AN: 280

European-Non Finnish (NFE) AF: 0.358 AC: 23914 AN: 66874

Other (OTH) AF: 0.291 AC: 587 AN: 2020

Alfa AF: 0.177 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
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: rs4016180; hg19: chr3-30733401; COSMIC: COSV55448035;