NM_004612.4:c.611C>T

Variant names:

• chr9-99137895-C-T
• rs886039068
• NM_004612.4:c.611C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004612.4(TGFBR1):​c.611C>T​(p.Thr204Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.86
• Publications: 1 publications found

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

TGFBR1 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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. 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
	TGFBR1	NM_004612.4	MANE Select	c.611C>T	p.Thr204Ile	missense	Exon 4 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.623C>T	p.Thr208Ile	missense	Exon 4 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.623C>T	p.Thr208Ile	missense	Exon 4 of 8	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.611C>T	p.Thr204Ile	missense	Exon 4 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.623C>T	p.Thr208Ile	missense	Exon 4 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.380C>T	p.Thr127Ile	missense	Exon 3 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial thoracic aortic aneurysm and aortic dissection (2)
-	1	-	Loeys-Dietz syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.46		Loss of sheet (P = 0.0817)
MVP		0.96
MPC		3.4
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.90
Mutation Taster		=2/98	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: rs886039068; hg19: chr9-101900177;