rs1553630181

Variant names:

• chr3-30672111-G-A
• rs1553630181
• NM_003242.6:c.928G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-30672111-G-A
• chr3-30672111-G-T
• chr3-30672111-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_003242.6(TGFBR2):​c.928G>A​(p.Ala310Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A310S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 2, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

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.928G>A	p.Ala310Thr	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1111G>A	p.Ala371Thr	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1036G>A	p.Ala346Thr	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.928G>A	p.Ala310Thr	missense	Exon 4 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1003G>A	p.Ala335Thr	missense	Exon 5 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.928G>A	p.Ala310Thr	missense	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial thoracic aortic aneurysm and aortic dissection (3)
-	1	-	Loeys-Dietz syndrome 2 (1)
-	1	-	Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.2	L
PhyloP100		10
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.46
Sift	Benign	0.070	T
Sift4G	Benign	0.10	T
Polyphen		0.95	P
Vest4		0.90
MVP		0.90
MPC		1.3
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.63
gMVP		0.75
Mutation Taster		=31/69	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: rs1553630181; hg19: chr3-30713603;