9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004612.4(TGFBR1):c.70_78delGCGGCGGCG(p.Ala24_Ala26del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0928 in 1,043,304 control chromosomes in the GnomAD database, including 4,897 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 585 hom., cov: 30)

Exomes 𝑓: 0.095 ( 4312 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 2.84

Publications

24 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 -16 ACMG points.

BP6

Variant 9-99105255-TGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 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.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0815

AC:

11610

AN:

142372

Hom.:

586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0589

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0629

Gnomad ASJ

AF:

0.0784

Gnomad EAS

AF:

0.00165

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.0909

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0903

GnomAD2 exomes

AF:

0.0582

AC:

AN:

584

AF XY:

0.0765

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0837

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0946

AC:

85196

AN:

900830

Hom.:

4312

AF XY:

0.0941

AC XY:

39758

AN XY:

422658

show subpopulations

African (AFR)

AF:

0.0552

AC:

959

AN:

17388

American (AMR)

AF:

0.0378

AC:

106

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.0589

AC:

430

AN:

7300

East Asian (EAS)

AF:

0.000434

AC:

AN:

9216

South Asian (SAS)

AF:

0.0375

AC:

678

AN:

18062

European-Finnish (FIN)

AF:

0.0807

AC:

415

AN:

5140

Middle Eastern (MID)

AF:

0.0605

AC:

118

AN:

1952

European-Non Finnish (NFE)

AF:

0.0991

AC:

80010

AN:

807642

Other (OTH)

AF:

0.0790

AC:

2476

AN:

31326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

4712

9424

14135

18847

23559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3866

7732

11598

15464

19330

<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:

0.0815

AC:

11615

AN:

142474

Hom.:

585

Cov.:

AF XY:

0.0812

AC XY:

5633

AN XY:

69374

show subpopulations

African (AFR)

AF:

0.0589

AC:

2314

AN:

39314

American (AMR)

AF:

0.0628

AC:

914

AN:

14550

Ashkenazi Jewish (ASJ)

AF:

0.0784

AC:

262

AN:

3342

East Asian (EAS)

AF:

0.00166

AC:

AN:

4824

South Asian (SAS)

AF:

0.0363

AC:

167

AN:

4604

European-Finnish (FIN)

AF:

0.137

AC:

1117

AN:

8136

Middle Eastern (MID)

AF:

0.0909

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.102

AC:

6562

AN:

64606

Other (OTH)

AF:

0.0893

AC:

177

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

494

988

1482

1976

2470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0343

Hom.:

Bravo

AF:

0.0738

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1, BS1, BP3, BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), has an allele frequency that is greater than expected for the associated disease, is an in-frame deletion/insertion in a repetitive region without a known function, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Dec 23, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 21, 2013

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome 1

Uncertain:1Benign:1

Dec 19, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome

Benign:2

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Jul 09, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thoracic aortic aneurysm

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=197/3

polymorphism (auto)

(source)

Splicing

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