chr9-99138041-A-G

Variant names:

• chr9-99138041-A-G
• rs886038919
• NM_004612.4:c.757A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_004612.4(TGFBR1):​c.757A>G​(p.Met253Val) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Protein kinase (size 290) in uniprot entity TGFR1_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TGFBR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 2.7935 (below the threshold of 3.09). Trascript score misZ: 3.6468 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, multiple self-healing squamous epithelioma, Loeys-Dietz syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 9-99138041-A-G is Pathogenic according to our data. Variant chr9-99138041-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 263773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.757A>G	p.Met253Val	missense_variant	Exon 4 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.757A>G	p.Met253Val	missense_variant	Exon 4 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Jul 07, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M253V variant (also known as c.757A>G) is located in coding exon 4 of the TGFBR1 gene in the protein kinase domain. This alteration results from an A to G substitution at nucleotide position 757. The methionine at codon 253 is replaced by valine, an amino acid with some highly similar properties, and is located in a protein kinase domain. This variant has been identified in an individual with Loeys-Dietz syndrome symptoms (Ambry internal data). Another alteration at the same codon, p.M253I (c.759G>A) has been reported in individuals with Marfan syndrome and Loeys-Dietz syndrome, with segregation of disease reported in at least one family (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Beckmann E et al. Ann. Thorac. Surg., 2014 May;97:e125-7; Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 253 of the TGFBR1 protein (p.Met253Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFBR1-related conditions (external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 263773). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TGFBR1 protein function with a positive predictive value of 80%. This variant disrupts the p.Met253 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16799921, 18781618, 31624717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Marfan syndrome Pathogenic:1

Sep 27, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome Pathogenic:1

May 31, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;.;D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	L;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.57	P;P;.;.;.
Vest4		0.85
MutPred		0.66		Loss of phosphorylation at Y249 (P = 0.1997);.;.;.;.;
MVP		0.95
MPC		2.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs886038919; hg19: chr9-101900323;