9-99128971-A-T

Variant names:

• chr9-99128971-A-T
• rs111513627
• NM_004612.4:c.214A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004612.4(TGFBR1):​c.214A>T​(p.Ile72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000256 in 1,613,910 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I72V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 4.10
• Publications: 5 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1676732).
• BP6: Variant 9-99128971-A-T is Benign according to our data. Variant chr9-99128971-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178136.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000263 (384/1461712) while in subpopulation NFE AF = 0.00033 (367/1111926). AF 95% confidence interval is 0.000302. There are 0 homozygotes in GnomAdExome4. There are 186 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.214A>T	p.Ile72Leu	missense_variant	Exon 2 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.214A>T	p.Ile72Leu	missense_variant	Exon 2 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000338

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 250904 AF XY: 0.000214

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 186 AN XY: 727152

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.000179 AC: 8 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000330 AC: 367 AN: 1111926

Other (OTH) AF: 0.000116 AC: 7 AN: 60380

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74348

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26017485, 27153395) -

Mar 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR1 c.214A>T; p.Ile72Leu variant (rs111513627) is reported in the literature in several individuals affected with abdominal aortic aneurysm, bicuspid aortic valve, or a connective tissue disorder; however, its clinical significance was not demonstrated in these individuals (Bonachea 2014, van de Luijtgaarden 2015, Weerakkody 2016). In one family affected with aortic aneurysm, the p.Ile72Leu variant did not segregate with disease (van de Luijtgaarden 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.03% (44/128734 alleles) in the Genome Aggregation Database. The isoleucine at codon 72 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.351). Due to limited information, the clinical significance of the p.Ile72Leu variant is uncertain at this time. References: Bonachea EM et al. Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve. BMC Med Genomics. 2014 Sep 26;7:56. van de Luijtgaarden KM et al. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet. 2015 Aug;134(8):881-93. Weerakkody RA et al. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome. Genet Med. 2016 Nov;18(11):1119-1127. -

May 03, 2017

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:3

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I72L variant (also known as c.214A>T), located in coding exon 2 of the TGFBR1 gene, results from an A to T substitution at nucleotide position 214. The isoleucine at codon 72 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in abdominal aortic aneurysm (AAA) and connective tissue disease cohorts, but was reported not to segregate with AAA in at least one family (van de Luijtgaarden KM et al. Hum. Genet., 2015 Aug;134:881-93; Weerakkody RA et al. Genet. Med., 2016 11;18:1119-1127). This amino acid position is well 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. -

Apr 05, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Jun 24, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Ile72Leu varian t in TGFBR1 has not been reported in individuals with clinical features of Loeys -Dietz syndrome, but has been identified in 0.1% (1/1126) of chromosomes from a clinically and racially unspecified population, and in 0.03% (3/8600) of Europea n American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs111513627). While this frequency suggests that this var iant is more likely benign, it is too low to confidently rule out a disease caus ing role. Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of the Ile72Leu variant. -

Oct 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFBR1 c.214A>T (p.Ile72Leu) results in a conservative amino acid change located in the Activin types I and II receptor domain (IPR000472) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250904 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 290-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.214A>T has been reported in the literature in individuals affected with bicuspid aortic valve and unspecified connective tissue disease (Bonachea_2014, Weerakkody_2016), as well as abdominal aortic aneurysm in which the variant did not segregate in 1 family (van de Luijtgaarden_2015). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -

Ehlers-Danlos syndrome Uncertain:1

Mar 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TGFBR1-related disorder Uncertain:1

Apr 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR1 c.214A>T variant is predicted to result in the amino acid substitution p.Ile72Leu. This variant was reported as a variant of uncertain significance in two individuals with abdominal aortic aneurysms (van de Luijtgaarden et al. 2015. PubMed ID: 26017485) and in an individual with unspecified hereditary connective tissue disorder (Weerakkody et al. 2016. PubMed ID: 27011056). This variant resides outside of the serine-threonine kinase domain, which contains the majority of pathogenic missense variants (amino acids 206-496; Wrana et al. 1994. PubMed ID: 8047140). This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101891253-A-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/178136/). Although we suspect this variant is more likely to be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;D;.;.;T;.;.;T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.69	.;.;N;N;N;.;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D;T;T;T;D;D;T;.
Sift4G	Uncertain	0.038	D;T;T;T;T;D;T;T;T
Polyphen		0.0, 0.026, 0.95	.;.;B;B;.;.;P;.;.
Vest4		0.35, 0.34, 0.34, 0.38
MutPred		0.52		.;.;Loss of catalytic residue at L77 (P = 0.062);Loss of catalytic residue at L77 (P = 0.062);Loss of catalytic residue at L77 (P = 0.062);.;.;.;.;
MVP		0.61
MPC		0.52
ClinPred		0.12	T
GERP RS		6.1
Varity_R		0.66
gMVP		0.88
Mutation Taster		=74/26	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: rs111513627; hg19: chr9-101891253;