9-99105215-G-A

Variant names:

• chr9-99105215-G-A
• rs1429700300
• NM_004612.4:c.10G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004612.4(TGFBR1):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 933,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• Publications: 0 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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.293916).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000225 AC: 21 AN: 933992 Hom.: 0 Cov.: 30 AF XY: 0.0000274 AC XY: 12 AN XY: 438652

African (AFR) AF: 0.00 AC: 0 AN: 18410

American (AMR) AF: 0.00 AC: 0 AN: 3622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8702

East Asian (EAS) AF: 0.00 AC: 0 AN: 12618

South Asian (SAS) AF: 0.00 AC: 0 AN: 18272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2162

European-Non Finnish (NFE) AF: 0.0000253 AC: 21 AN: 828538

Other (OTH) AF: 0.00 AC: 0 AN: 33644

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4 of the TGFBR1 protein (p.Ala4Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		1.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.51	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.20	T;D;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.25	B;P;.
Vest4		0.22
MutPred		0.33		Gain of glycosylation at A4 (P = 0.0055);Gain of glycosylation at A4 (P = 0.0055);Gain of glycosylation at A4 (P = 0.0055);
MVP		0.68
MPC		0.50
ClinPred		0.58	D
GERP RS		2.7
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.039
gMVP		0.48
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: rs1429700300; hg19: chr9-101867497;