Genetic Variant TGFBR1:p.Met318Arg (chr9-99142683-T-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_004612.4(TGFBR1):c.953T>G(p.Met318Arg) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M318V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TGFBR1
NM_004612.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.02

Publications

19 publications found

Variant links:

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

TGFBR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_004612.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 9-99142683-T-G is Pathogenic according to our data. Variant chr9-99142683-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12520.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	NM_004612.4	MANE Select	c.953T>G	p.Met318Arg	missense	Exon 5 of 9	NP_004603.1	P36897-1
TGFBR1	NM_001306210.2		c.965T>G	p.Met322Arg	missense	Exon 5 of 9	NP_001293139.1	P36897-2
TGFBR1	NM_001407418.1		c.758T>G	p.Met253Arg	missense	Exon 5 of 9	NP_001394347.1	F8W0K6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.953T>G	p.Met318Arg	missense	Exon 5 of 9	ENSP00000364133.4	P36897-1
TGFBR1	ENST00000552516.5	TSL:1	c.965T>G	p.Met322Arg	missense	Exon 5 of 9	ENSP00000447297.1	P36897-2
TGFBR1	ENST00000374990.6	TSL:1	c.722T>G	p.Met241Arg	missense	Exon 4 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Loeys-Dietz syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.47

PhyloP100

8.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.029

Polyphen

0.99

Vest4

0.93

MutPred

0.80

Loss of catalytic residue at H317 (P = 0.1123)

MVP

0.91

MPC

2.0

ClinPred

0.98

GERP RS

5.9

Varity_R

0.95

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over