3-30691909-TTATATATATA-TTATATATATATATATA

Variant names:

• chr3-30691909-T-TTATATA
• rs4016180
• NM_003242.6:c.*324_*329dupATATAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003242.6(TGFBR2):​c.*324_*329dupATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000136 (20/147360) while in subpopulation AFR AF = 0.000326 (13/39900). AF 95% confidence interval is 0.000192. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 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.*324_*329dupATATAT		3_prime_UTR	Exon 7 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.*324_*329dupATATAT		3_prime_UTR	Exon 9 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.*324_*329dupATATAT		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.*324_*329dupATATAT		3_prime_UTR	Exon 7 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.*324_*329dupATATAT		3_prime_UTR	Exon 8 of 8	ENSP00000351905.4
	TGFBR2	ENST00000941789.1		c.*324_*329dupATATAT		3_prime_UTR	Exon 7 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.000136 AC: 20 AN: 147324 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000999 AC: 1 AN: 100116 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 49628

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

African (AFR) AF: 0.00 AC: 0 AN: 4062

American (AMR) AF: 0.000190 AC: 1 AN: 5250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4698

East Asian (EAS) AF: 0.00 AC: 0 AN: 12364

South Asian (SAS) AF: 0.00 AC: 0 AN: 6772

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57898

Other (OTH) AF: 0.00 AC: 0 AN: 6942

⚠️ 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: 0.000136 AC: 20 AN: 147360 Hom.: 0 Cov.: 0 AF XY: 0.0000558 AC XY: 4 AN XY: 71738

African (AFR) AF: 0.000326 AC: 13 AN: 39900

American (AMR) AF: 0.000271 AC: 4 AN: 14760

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

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5076

South Asian (SAS) AF: 0.000213 AC: 1 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: 0.0000149 AC: 1 AN: 66960

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.00 Hom.: 277

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16

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;