rs925777307

Positions:

• chr9-99149231-G-A
• chr9-99149231-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_004612.4(TGFBR1):​c.1438G>A​(p.Ala480Thr) 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 benign 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:3
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 gene, where missense usually causes diseases (based on misZ statistic), TGFBR1. . Gene score misZ 2.7935 (greater than the threshold 3.09). Trascript score misZ 3.6468 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, multiple self-healing squamous epithelioma, Loeys-Dietz syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28321478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.1438G>A	p.Ala480Thr	missense_variant	9/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1438G>A	p.Ala480Thr	missense_variant	9/9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR1 protein function. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 480 of the TGFBR1 protein (p.Ala480Thr). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2023	The p.A480T variant (also known as c.1438G>A), located in coding exon 9 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 1438. The alanine at codon 480 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.81	L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.030	D;D;T;D
Sift4G	Benign	0.099	T;T;T;T
Polyphen		0.28	B;B;.;.
Vest4		0.44
MutPred		0.41		Gain of solvent accessibility (P = 0.28);.;.;.;
MVP		0.60
MPC		1.3
ClinPred		0.86	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.58

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: rs925777307; hg19: chr9-101911513;