rs141259922

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:5

Conservation

PhyloP100: 9.32

Publications

15 publications found

Variant links:

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

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_004612.4

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 VariationId is 161393.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000342 (52/152162) while in subpopulation AMR AF = 0.000786 (12/15268). AF 95% confidence interval is 0.000453. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.1433A>G	p.Asn478Ser	missense_variant	Exon 9 of 9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 link	c.1433A>G	p.Asn478Ser	missense_variant	Exon 9 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000291

AC:

AN:

250492

AF XY:

0.000288

show subpopulations

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 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.:

Cov.:

AF XY:

0.000319

AC XY:

232

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.000134

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26114

East Asian (EAS)

AF:

0.000126

AC:

AN:

39678

South Asian (SAS)

AF:

0.000186

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000333

AC:

370

AN:

1111774

Other (OTH)

AF:

0.000166

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000342

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41428

American (AMR)

AF:

0.000786

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68036

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.000382

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3Benign:1

Feb 15, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 clinical features of TGFBR1-related conditions (PMID: 16928994, 25116393, 25907466, 25985138, 28550590). This variant is also known as c.1202A>G (p.N401S). ClinVar contains an entry for this variant (Variation ID: 161393). 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. -

Nov 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 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. -

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:3Benign:1

Nov 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.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. -

Dec 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published in association with Loeys-Dietz syndrome (LDS) and thoracic aortic disease, though not all publications included patient-specific data (PMID: 25116393, 16928994, 25985138, 25907466, 27879313, 28550590); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(N401S); This variant is associated with the following publications: (PMID: 21358634, 27879313, 17061023, 27153395, 25985138, 25637381, 25907466, 27647783, 24055113, 34426522, 28550590, 25116393, 16928994, 36937954) -

Oct 28, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGFBR1: PM1, BS1 -

not specified

Benign:3

Mar 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 09, 2024

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.1433A>G (p.Asn478Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) 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 0.00029 in 250492 control chromosomes. The observed variant frequency is approximately 156 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06), strongly suggesting that the variant is benign. c.1433A>G has been reported in the literature in individuals affected with Loeys-Dietz Syndrome and unspecified neurodevelopmental diseases, without strong evidence for causality (Alotibi_2023, Loeys_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36937954, 16928994). ClinVar contains an entry for this variant (Variation ID: 161393). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome 1

Uncertain:2

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 21, 2022

Revvity Omics, Revvity

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

Jan 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome

Uncertain:1

Sep 23, 2024

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 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

Jul 22, 2020

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

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.9

L;.;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

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

GERP RS

5.7

Varity_R

0.46

gMVP

0.69

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over