rs200018073

Variant names:

• chr9-99137897-A-G
• rs200018073
• NM_004612.4:c.613A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-99137897-A-G
• chr9-99137897-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_004612.4(TGFBR1):​c.613A>G​(p.Ile205Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• 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 Likely_benign. Variant got -1 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
• 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.
• BS2: High AC in GnomAdExome4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.613A>G	p.Ile205Val	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.613A>G	p.Ile205Val	missense_variant	Exon 4 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251306 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:4

Nov 29, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I205V variant (also known as c.613A>G), located in coding exon 4 of the TGFBR1 gene, results from an A to G substitution at nucleotide position 613. The isoleucine at codon 205 is replaced by valine, an amino acid with highly similar properties, and is in the protein kinase domain. Another alteration affecting this amino acid, p.I205M (c.615T>G), was reported in a study of clinical genetic testing; however, clinical details were limited (Pepin MG et al. Genet. Med., 2016 Jan;18:20-4). 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. -

Jul 24, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 205 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 205 of the TGFBR1 protein (p.Ile205Val). This variant is present in population databases (rs200018073, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 213899). 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 not expected to disrupt TGFBR1 protein function with a negative predictive value of 80%. 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. -

Sep 29, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Uncertain:1

Oct 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 1 Uncertain:1

May 11, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome Uncertain:1

Oct 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 205 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Feb 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.65	N;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.63	N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.79	P;B;.;.;.
Vest4		0.46
MutPred		0.55		Gain of catalytic residue at I205 (P = 0.01);.;.;.;.;
MVP		0.86
MPC		2.9
ClinPred		0.25	T
GERP RS		5.6
Varity_R		0.43
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs200018073; hg19: chr9-101900179;