rs17854016

Variant names:

• chr3-30672186-G-C
• rs17854016
• NM_003242.6:c.1003G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-30672186-G-C
• chr3-30672186-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003242.6(TGFBR2):​c.1003G>C​(p.Glu335Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,012 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 91 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.2437 (below the threshold of 3.09). Trascript score misZ: 2.9378 (below the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 2.

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.1003G>C	p.Glu335Gln	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1186G>C	p.Glu396Gln	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1111G>C	p.Glu371Gln	missense	Exon 5 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.1003G>C	p.Glu335Gln	missense	Exon 4 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1078G>C	p.Glu360Gln	missense	Exon 5 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.1003G>C	p.Glu335Gln	missense	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461012 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726616

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111216

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.070	N
PhyloP100		10
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		0.64	P
Vest4		0.61
MutPred		0.70		Gain of MoRF binding (P = 0.0519)
MVP		1.0
MPC		1.1
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.75
Mutation Taster		=21/79	disease causing

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: rs17854016; hg19: chr3-30713678;