chr3-30691909-TTATATA-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003242.6(TGFBR2):​c.*324_*329delATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 247,402 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000068 (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: 2.05
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.*324_*329delATATAT		3_prime_UTR	Exon 7 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.*324_*329delATATAT		3_prime_UTR	Exon 9 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.*324_*329delATATAT		3_prime_UTR	Exon 8 of 8	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.*324_*329delATATAT		3_prime_UTR	Exon 7 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.*324_*329delATATAT		3_prime_UTR	Exon 8 of 8	ENSP00000351905.4
	TGFBR2	ENST00000672050.1		n.912_*2delATATAT		splice_region non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147324 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

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: 100078 Hom.: 0 AF XY: 0.0000202 AC XY: 1 AN XY: 49606

⚠️ 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: 0.00 AC: 0 AN: 5250

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

East Asian (EAS) AF: 0.0000809 AC: 1 AN: 12362

South Asian (SAS) AF: 0.00 AC: 0 AN: 6768

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: 57870

Other (OTH) AF: 0.00 AC: 0 AN: 6938

⚠️ 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: 0.00000679 AC: 1 AN: 147324 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71690

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

African (AFR) AF: 0.00 AC: 0 AN: 39832

American (AMR) AF: 0.00 AC: 0 AN: 14746

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66970

Other (OTH) AF: 0.00 AC: 0 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
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;