9-99105255-TGGCGGC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_004612.4(TGFBR1):c.73_78delGCGGCG(p.Ala25_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 0.0000441 in 1,043,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000070 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004612.4

BP6

Variant 9-99105255-TGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.73_78delGCGGCG	p.Ala25_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.73_78delGCGGCG	p.Ala25_Ala26del	conservative_inframe_deletion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0000702

AC:

AN:

142424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000688

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.000217

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00347

Gnomad NFE

AF:

0.0000619

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000400

AC:

AN:

900942

Hom.:

AF XY:

0.0000402

AC XY:

AN XY:

422746

show subpopulations

African (AFR)

AF:

0.000345

AC:

AN:

17388

American (AMR)

AF:

0.00

AC:

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.000137

AC:

AN:

7300

East Asian (EAS)

AF:

0.000109

AC:

AN:

9214

South Asian (SAS)

AF:

0.000111

AC:

AN:

18064

European-Finnish (FIN)

AF:

0.000194

AC:

AN:

5142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.0000272

AC:

AN:

807748

Other (OTH)

AF:

0.0000958

AC:

AN:

31330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

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:

0.0000702

AC:

AN:

142524

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

69398

show subpopulations

African (AFR)

AF:

0.0000254

AC:

AN:

39328

American (AMR)

AF:

0.0000687

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.000415

AC:

AN:

4824

South Asian (SAS)

AF:

0.000217

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00376

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000619

AC:

AN:

64622

Other (OTH)

AF:

0.00

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Feb 14, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2015

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. -

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TGFBR1-related disorder

Benign:1

Sep 13, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

May 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=188/12

polymorphism

(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