3-30691909-TTATATATATA-TTATATATATATATA

Variant names:

• chr3-30691909-T-TTATA
• rs4016180
• NM_003242.6:c.*326_*329dupATAT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_003242.6(TGFBR2):​c.*326_*329dupATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.163
• 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 -9 ACMG points.

• BP6: Variant 3-30691909-T-TTATA is Benign according to our data. Variant chr3-30691909-T-TTATA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344669.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00272 (401/147342) while in subpopulation AFR AF = 0.00852 (340/39884). AF 95% confidence interval is 0.00778. There are 1 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 401 AD gene.

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.*326_*329dupATAT		3_prime_UTR	Exon 7 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.*326_*329dupATAT		3_prime_UTR	Exon 9 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.*326_*329dupATAT		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.*326_*329dupATAT		3_prime_UTR	Exon 7 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.*326_*329dupATAT		3_prime_UTR	Exon 8 of 8	ENSP00000351905.4
	TGFBR2	ENST00000941789.1		c.*326_*329dupATAT		3_prime_UTR	Exon 7 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 399 AN: 147306 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00196

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000343

Gnomad OTH AF: 0.00249

GnomAD4 exome AF: 0.000390 AC: 39 AN: 100082 Hom.: 0 Cov.: 0 AF XY: 0.000343 AC XY: 17 AN XY: 49616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00271 AC: 11 AN: 4054

American (AMR) AF: 0.00 AC: 0 AN: 5244

Ashkenazi Jewish (ASJ) AF: 0.000213 AC: 1 AN: 4698

East Asian (EAS) AF: 0.000162 AC: 2 AN: 12362

South Asian (SAS) AF: 0.000443 AC: 3 AN: 6772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1620

Middle Eastern (MID) AF: 0.00394 AC: 2 AN: 508

European-Non Finnish (NFE) AF: 0.000225 AC: 13 AN: 57884

Other (OTH) AF: 0.00101 AC: 7 AN: 6940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00272 AC: 401 AN: 147342 Hom.: 1 Cov.: 0 AF XY: 0.00252 AC XY: 181 AN XY: 71732

African (AFR) AF: 0.00852 AC: 340 AN: 39884

American (AMR) AF: 0.00102 AC: 15 AN: 14760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00197 AC: 10 AN: 5076

South Asian (SAS) AF: 0.00171 AC: 8 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000343 AC: 23 AN: 66958

Other (OTH) AF: 0.00247 AC: 5 AN: 2022

Alfa AF: 0.000112 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Loeys-Dietz syndrome (1)
-	1	-	Marfan syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4016180; hg19: chr3-30733401;