3-30606689-G-A

Variant names:

• chr3-30606689-G-A
• rs925186023
• NM_003242.6:c.-195G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003242.6(TGFBR2):​c.-195G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000845 in 236,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45
• Publications: 0 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):

• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105377015 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).

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.-195G>A		5_prime_UTR	Exon 1 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.-195G>A		5_prime_UTR	Exon 1 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.-195G>A		5_prime_UTR	Exon 1 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.-195G>A		5_prime_UTR	Exon 1 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.-195G>A		5_prime_UTR	Exon 1 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.-195G>A		5_prime_UTR	Exon 1 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000845 AC: 2 AN: 236548 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 119294

African (AFR) AF: 0.00 AC: 0 AN: 6894

American (AMR) AF: 0.000147 AC: 1 AN: 6782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8786

East Asian (EAS) AF: 0.00 AC: 0 AN: 22146

South Asian (SAS) AF: 0.00 AC: 0 AN: 2256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1204

European-Non Finnish (NFE) AF: 0.00000654 AC: 1 AN: 152978

Other (OTH) AF: 0.00 AC: 0 AN: 15466

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
PhyloP100		3.4
PromoterAI		0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs925186023; hg19: chr3-30648181;