rs768385200

Variant names:

• chr3-30650373-A-T
• rs768385200
• NM_003242.6:c.367A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_003242.6(TGFBR2):​c.367A>T​(p.Met123Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5 O:2
• Conservation: PhyloP100: 7.79
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• 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.
• BP6: Variant 3-30650373-A-T is Benign according to our data. Variant chr3-30650373-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213939.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152112) while in subpopulation AMR AF = 0.00072 (11/15286). AF 95% confidence interval is 0.000403. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 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.367A>T	p.Met123Leu	missense	Exon 3 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.442A>T	p.Met148Leu	missense	Exon 4 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.367A>T	p.Met123Leu	missense	Exon 3 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.367A>T	p.Met123Leu	missense	Exon 3 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.442A>T	p.Met148Leu	missense	Exon 4 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.367A>T	p.Met123Leu	missense	Exon 3 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151994 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250890 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727194

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111940

Other (OTH) AF: 0.000431 AC: 26 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67972

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Familial thoracic aortic aneurysm and aortic dissection (4)
-	3	-	not provided (3)
-	1	-	Diabetic retinopathy (1)
-	-	1	Loeys-Dietz syndrome (1)
-	1	-	Loeys-Dietz syndrome 2 (1)
-	-	1	Marfan syndrome (1)
-	1	-	not specified (1)
-	-	-	Loeys-Dietz syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	D
Sift4G	Benign	0.25	T
Polyphen		0.78	P
Vest4		0.59
MutPred		0.71		Gain of methylation at K124 (P = 0.0339)
MVP		0.89
MPC		1.3
ClinPred		0.25	T
GERP RS		6.0
Varity_R		0.73
gMVP		0.68
Mutation Taster		=60/40	polymorphism

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: rs768385200; hg19: chr3-30691865;