chr9-99105255-T-TGGCGGCGGCGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004612.4(TGFBR1):​c.64_78dupGCGGCGGCGGCGGCG​(p.Ala22_Ala26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 142,526 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000011 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TGFBR1
NM_004612.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.987

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR1NM_004612.4 linkc.64_78dupGCGGCGGCGGCGGCG p.Ala22_Ala26dup conservative_inframe_insertion Exon 1 of 9 ENST00000374994.9 NP_004603.1 P36897-1Q5T7S2B4DXN7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFBR1ENST00000374994.9 linkc.64_78dupGCGGCGGCGGCGGCG p.Ala22_Ala26dup conservative_inframe_insertion Exon 1 of 9 1 NM_004612.4 ENSP00000364133.4 P36897-1

Frequencies

GnomAD3 genomes
AF:
0.0000140
AC:
2
AN:
142424
Hom.:
0
Cov.:
30
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000111
AC:
1
AN:
900970
Hom.:
0
Cov.:
7
AF XY:
0.00
AC XY:
0
AN XY:
422764
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:
0
AN:
17388
American (AMR)
AF:
0.00
AC:
0
AN:
2804
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
7300
East Asian (EAS)
AF:
0.00
AC:
0
AN:
9216
South Asian (SAS)
AF:
0.0000554
AC:
1
AN:
18064
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5144
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1952
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
807770
Other (OTH)
AF:
0.00
AC:
0
AN:
31332
⚠️ 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: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000140
AC:
2
AN:
142526
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
69400
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000254
AC:
1
AN:
39330
American (AMR)
AF:
0.0000687
AC:
1
AN:
14554
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3342
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4824
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4608
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8144
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
266
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
64622
Other (OTH)
AF:
0.00
AC:
0
AN:
1984
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
37

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Sep 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.64_78dup, results in the insertion of 5 amino acid(s) of the TGFBR1 protein (p.Ala22_Ala26dup), 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 been observed in individual(s) with TGFBR1-related disorder (PMID: 29510914). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.99
Mutation Taster
=73/27
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs11466445; hg19: chr9-101867537; API