9-99105255-TGGCGGCGGCGGCGGC-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004612.4(TGFBR1):c.64_78delGCGGCGGCGGCGGCG(p.Ala22_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 0.000023 in 1,043,388 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 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:3

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 -1 ACMG points.

BP6

Variant 9-99105255-TGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 496263.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.64_78delGCGGCGGCGGCGGCG	p.Ala22_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.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0000211

AC:

AN:

142422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000464

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

900966

Hom.:

AF XY:

0.0000331

AC XY:

AN XY:

422760

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

17388

American (AMR)

AF:

0.00

AC:

AN:

2804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7300

East Asian (EAS)

AF:

0.00

AC:

AN:

9216

South Asian (SAS)

AF:

0.000111

AC:

AN:

18064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.0000223

AC:

AN:

807766

Other (OTH)

AF:

0.0000319

AC:

AN:

31332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000212), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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:

0.0000211

AC:

AN:

142422

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39216

American (AMR)

AF:

0.00

AC:

AN:

14538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00

AC:

AN:

4840

South Asian (SAS)

AF:

0.00

AC:

AN:

4610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000464

AC:

AN:

64630

Other (OTH)

AF:

0.00

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The TGFBR1 c.64_78delGCGGCGGCGGCGGCG (p.Ala22_Ala26del) variant involves the deletion of 15 nucleotides and results an inframe deletion of 5 out of 9 consecutive Alanines in N-terminus of TGFBR1 protein. These repeating Alanines are not located in any known domain (InterPro). One in silico tool predicts a benign outcome for this variant. There is no or extremely low coverage in this region in control databases (ExAC, gnomAD, ESP, or 1000Gs). c.70_78delGCGGCGGCG (rs11466445), a shorter deletion in this Alanine repeat region, is classified as benign/likely benign by 8 clinical diagnostics laboratories in ClinVar. However, the variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Jul 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.64_78del, results in the deletion of 5 amino acid(s) of the TGFBR1 protein (p.Ala22_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 insufficient coverage 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: 496263). 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. -

Jun 16, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=157/43

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