rs141259922

Positions:

• chr9-99149226-A-G
• chr9-99149226-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_004612.4(TGFBR1):​c.1433A>G​(p.Asn478Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:2
• Conservation: PhyloP100: 9.32

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 -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_004612.4
• PP2: Missense variant where missense usually causes diseases, TGFBR1
• BP6: Variant 9-99149226-A-G is Benign according to our data. Variant chr9-99149226-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161393.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=12}. Variant chr9-99149226-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.1433A>G	p.Asn478Ser	missense_variant	9/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1433A>G	p.Asn478Ser	missense_variant	9/9	1	NM_004612.4	P4

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 250492 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000287 AC: 420 AN: 1461472 Hom.: 0 Cov.: 33 AF XY: 0.000319 AC XY: 232 AN XY: 727056

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000333

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74338

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000382

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 478 of the TGFBR1 protein (p.Asn478Ser). This variant is present in population databases (rs141259922, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Loeys-Dietz Syndrome (PMID: 16928994, 25116393, 25907466, 25985138). ClinVar contains an entry for this variant (Variation ID: 161393). 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This missense variant replaces asparagine with serine at codon 478 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 been reported in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 2511639, 25985138), in individuals affected with Marfan-related disorders (PMID: 21358634, 25907466, 28550590) and in individuals affected with thoracic aortic aneurysm (PMID: 25907466, 28550590). This variant has been reported in an unaffected individual and his son showing a phenotype that is not consistent with Loeys-Dietz syndrome (Alsubaie 2018). This variant occurs at an appreciable frequency in the general population and has been identified in 77/281886 chromosomes (61/128464 non-Finnish European chromosomes) 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2022	The p.N478S variant (also known as c.1433A>G), located in coding exon 9 of the TGFBR1 gene, results from an A to G substitution at nucleotide position 1433. The asparagine at codon 478 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in Loeys-Dietz syndrome cohorts and thoracic aortic aneurysm and dissection (TAAD) cohorts; however, clinical details were limited in some cases (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Wellbrock J et al. PLoS ONE, 2014 Aug;9:e104742); Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Taylor JC et al. Nat. Genet., 2015 Jul;47:717-726: Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). 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. -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TGFBR1: PM1, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	The TGFBR1 c.1433A>G; p.Asn478Ser variant (rs141259922), also known as N401S, is reported in individuals with Loeys-Dietz syndrome or thoracic aortic aneurysm and dissection (Loeys 2006, Proost 2015, Wellbrock 2014). In one individual with Loeys-Dietz syndrome, the variant was also detected in their unaffected father (Loeys 2006). The p.Asn478Ser variant is reported in ClinVar (Variation ID: 161393). It is observed in the general population with an overall allele frequency of 0.027% (77/281886 alleles) in the Genome Aggregation Database (v.2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Loeys BL et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. PMID: 16928994. Proost D et al. Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. Hum Mutat. 2015 Aug;36(8):808-14. PMID: 25907466. Wellbrock J et al. Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. PLoS One. 2014 Aug 12;9(8):e104742. PMID: 25116393. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	Initially identified in a child with LDS and her unaffected father (Loeys et al., 2006); Published in association with Loeys-Dietz syndrome (LDS) and thoracic aortic disease, though not all publications included patient-specific data; also referred to as N401S due to alternate nomenclature (Loeys et al., 2006; Wellbrock et al., 2014; Taylor et al., 2015; Proost et al., 2015; Jondeau et al., 2016; Landis et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21358634, 27879313, 17061023, 27153395, 25985138, 25637381, 25907466, 27647783, 24055113, 34426522, 25116393, 28550590, 16928994) -

Loeys-Dietz syndrome 1 Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2022	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 07, 2022

- -

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces asparagine with serine at codon 478 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 been reported in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 2511639, 25985138), in individuals affected with Marfan-related disorders (PMID: 21358634, 25907466, 28550590) and in individuals affected with thoracic aortic aneurysm (PMID: 25907466, 28550590). This variant has been reported in an unaffected individual and his son showing a phenotype that is not consistent with Loeys-Dietz syndrome (Alsubaie 2018). This variant occurs at an appreciable frequency in the general population and has been identified in 77/281886 chromosomes (61/128464 non-Finnish European chromosomes) 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. -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 22, 2020

- -

TGFBR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The TGFBR1 c.1433A>G variant is predicted to result in the amino acid substitution p.Asn478Ser. This variant was reported in at least two individuals with Loeys-Dietz syndrome, in one of the cases this variant was found also in an unaffected father (Loeys et al. 2006. PubMed ID: 16928994; Wellbrock et al. 2014. PubMed ID: 25116393). This variant was also reported in an individual with thoracic aortic aneurysm (Proost et al. 2015. PubMed ID: 25907466). Furthermore, this variant was reported as a variant of unknown significance by large exome and genome studies, documented as an incidental finding (reported as p.Asn401Ser; Amendola et al. 2015. PubMed ID: 25637381 Table S1; Taylor et al. 2015. PubMed ID: 25985138 Table S10) and by an exome study of families with breast cancer (Maxwell et al. 2016. PubMed ID: 27153395 Table S5). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD , which is higher than would be expected for causative variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2018

p.Asn478Ser in exon 9 of TGFBR1: This variant is not expected to have clinical significance because it has been identified in 0.05% (59/125980) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141259922) and in 2 unaffected parents (Loeys 2006). ACMG/AMP Criteria applied: BS2; BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.078	T;T;T;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.21	B;B;.;.
Vest4		0.90
MVP		0.89
MPC		1.4
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.46
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141259922; hg19: chr9-101911508;