3-30672342-G-T

Variant names:

• chr3-30672342-G-T
• rs35766612
• NM_003242.6:c.1159G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_003242.6(TGFBR2):​c.1159G>T​(p.Val387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,613,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V387M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:9
• Conservation: PhyloP100: 8.05
• Publications: 40 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.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_003242.6
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08301011).
• BP6: Variant 3-30672342-G-T is Benign according to our data. Variant chr3-30672342-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36862.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000355 (54/152170) while in subpopulation NFE AF = 0.000514 (35/68030). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 54 AD,Unknown 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.1159G>T	p.Val387Leu	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1342G>T	p.Val448Leu	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1267G>T	p.Val423Leu	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.1159G>T	p.Val387Leu	missense	Exon 4 of 7	ENSP00000295754.5	P37173-1
	TGFBR2	ENST00000359013.4	TSL:1	c.1234G>T	p.Val412Leu	missense	Exon 5 of 8	ENSP00000351905.4	P37173-2
	TGFBR2	ENST00000941789.1		c.1159G>T	p.Val387Leu	missense	Exon 4 of 7	ENSP00000611848.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000351 AC: 88 AN: 250480 AF XY: 0.000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000354 AC: 517 AN: 1461476 Hom.: 1 Cov.: 34 AF XY: 0.000399 AC XY: 290 AN XY: 727044

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 79 AN: 26060

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86226

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000309 AC: 344 AN: 1111780

Other (OTH) AF: 0.000447 AC: 27 AN: 60370

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74330

African (AFR) AF: 0.0000483 AC: 2 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68030

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.0000469 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	3	not specified (3)
-	1	1	not provided (2)
-	1	-	Ehlers-Danlos syndrome (1)
-	1	-	Loeys-Dietz syndrome (1)
-	-	1	TGFBR2-related disorder (1)
-	1	-	Vascular dilatation;C0856747:Ascending tubular aorta aneurysm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.083	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.47	N
PhyloP100		8.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.54
Sift	Benign	0.82	T
Sift4G	Benign	0.69	T
Polyphen		0.94	P
Vest4		0.49
MutPred		0.73		Loss of methylation at K388 (P = 0.0335)
MVP		0.92
MPC		1.3
ClinPred		0.14	T
GERP RS		4.2
Varity_R		0.38
gMVP		0.75
Mutation Taster		=83/17	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: rs35766612; hg19: chr3-30713834; COSMIC: COSV55452433;