9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_004612.4(TGFBR1):c.67_78delGCGGCGGCGGCG(p.Ala23_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 0.0000776 in 1,043,432 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 9-99105255-TGGCGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 516727.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.67_78delGCGGCGGCGGCG	p.Ala23_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.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0000983

AC:

AN:

142424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000206

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000108

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000744

AC:

AN:

900906

Hom.:

AF XY:

0.0000781

AC XY:

AN XY:

422736

show subpopulations

African (AFR)

AF:

0.000115

AC:

AN:

17388

American (AMR)

AF:

0.000357

AC:

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7300

East Asian (EAS)

AF:

0.000109

AC:

AN:

9216

South Asian (SAS)

AF:

0.0000554

AC:

AN:

18064

European-Finnish (FIN)

AF:

0.000194

AC:

AN:

5142

Middle Eastern (MID)

AF:

0.000512

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.0000730

AC:

AN:

807708

Other (OTH)

AF:

0.0000319

AC:

AN:

31332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000982

AC:

AN:

142526

Hom.:

Cov.:

AF XY:

0.0000865

AC XY:

AN XY:

69400

show subpopulations

African (AFR)

AF:

0.0000509

AC:

AN:

39330

American (AMR)

AF:

0.000206

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:

0.00

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000108

AC:

AN:

64622

Other (OTH)

AF:

0.00

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.67_78del, results in the deletion of 4 amino acid(s) of the TGFBR1 protein (p.Ala23_Ala26del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 516727). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 15, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

TGFBR1-related disorder

Uncertain:1

Dec 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TGFBR1 c.67_78del12 variant is predicted to result in an in-frame deletion (p.Ala23_Ala26del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.29% of alleles (or four heterozygous alleles) in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101867537-TGGCGGCGGCGGC-T). The allele frequency data for this variant should be interpreted with caution due to insufficient coverage. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Aug 17, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=191/9

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