rs334354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004612.4(TGFBR1):c.1255+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,613,174 control chromosomes in the GnomAD database, including 38,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4034 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34404 hom. )

Consequence

TGFBR1
NM_004612.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.759

Publications

33 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 9-99146633-G-A is Benign according to our data. Variant chr9-99146633-G-A is described in ClinVar as Benign. ClinVar VariationId is 259451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.1255+24G>A		intron_variant	Intron 7 of 8	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.1255+24G>A		intron_variant	Intron 7 of 8	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34035

AN:

151990

Hom.:

4020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.222

GnomAD2 exomes

AF:

0.221

AC:

55348

AN:

251002

AF XY:

0.218

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.442

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.195

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.210

AC:

307479

AN:

1461066

Hom.:

34404

Cov.:

AF XY:

0.211

AC XY:

153060

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.250

AC:

8375

AN:

33436

American (AMR)

AF:

0.230

AC:

10304

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5184

AN:

26114

East Asian (EAS)

AF:

0.480

AC:

19035

AN:

39662

South Asian (SAS)

AF:

0.223

AC:

19260

AN:

86248

European-Finnish (FIN)

AF:

0.143

AC:

7646

AN:

53396

Middle Eastern (MID)

AF:

0.178

AC:

1027

AN:

5760

European-Non Finnish (NFE)

AF:

0.201

AC:

223428

AN:

1111386

Other (OTH)

AF:

0.219

AC:

13220

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

12902

25803

38705

51606

64508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7962

15924

23886

31848

39810

<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:

0.224

AC:

34091

AN:

152108

Hom.:

4034

Cov.:

AF XY:

0.222

AC XY:

16490

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.250

AC:

10375

AN:

41466

American (AMR)

AF:

0.244

AC:

3722

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

693

AN:

3472

East Asian (EAS)

AF:

0.432

AC:

2230

AN:

5168

South Asian (SAS)

AF:

0.223

AC:

1075

AN:

4828

European-Finnish (FIN)

AF:

0.143

AC:

1517

AN:

10582

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13812

AN:

67996

Other (OTH)

AF:

0.221

AC:

467

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1346

2692

4039

5385

6731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.211

Hom.:

1385

Bravo

AF:

0.230

Asia WGS

AF:

0.337

AC:

1171

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15382067, 22905183, 20354825, 16428477) -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome 1

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple self-healing squamous epithelioma

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.14

(source)

DANN

Benign

0.69

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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