9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004612.4(TGFBR1):c.76_78delGCG(p.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 0.0017 in 1,041,918 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 18 hom., cov: 30)

Exomes 𝑓: 0.00084 ( 6 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 9-99105255-TGGC-T is Benign according to our data. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGC-T is described in CliVar as Benign/Likely_benign. Clinvar id is 213863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00714 (1017/142520) while in subpopulation AFR AF = 0.0241 (948/39326). AF 95% confidence interval is 0.0228. There are 18 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 1017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.76_78delGCG	p.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.76_78delGCG	p.Ala26del	conservative_inframe_deletion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1001

AN:

142418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00296

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00174

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00694

Gnomad NFE

AF:

0.0000774

Gnomad OTH

AF:

0.00612

GnomAD2 exomes

AF:

0.00514

AC:

AN:

584

AF XY:

0.00588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0238

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000841

AC:

756

AN:

899398

Hom.:

AF XY:

0.000996

AC XY:

420

AN XY:

421838

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0205

AC:

355

AN:

17354

American (AMR)

AF:

0.00503

AC:

AN:

2782

Ashkenazi Jewish (ASJ)

AF:

0.000274

AC:

AN:

7288

East Asian (EAS)

AF:

0.00142

AC:

AN:

9170

South Asian (SAS)

AF:

0.00205

AC:

AN:

18008

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

5126

Middle Eastern (MID)

AF:

0.00155

AC:

AN:

1940

European-Non Finnish (NFE)

AF:

0.000337

AC:

272

AN:

806454

Other (OTH)

AF:

0.00150

AC:

AN:

31276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00714

AC:

1017

AN:

142520

Hom.:

Cov.:

AF XY:

0.00718

AC XY:

498

AN XY:

69398

show subpopulations

African (AFR)

AF:

0.0241

AC:

948

AN:

39326

American (AMR)

AF:

0.00295

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00

AC:

AN:

4824

South Asian (SAS)

AF:

0.00152

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00752

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

64620

Other (OTH)

AF:

0.00605

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGFBR1: BP3, BS1, BS2 -

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2018

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. -

Apr 11, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Apr 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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