9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3
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
NM_004612.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.987
Publications
24 publications found
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 dissectionInheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- Loeys-Dietz syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- Loeys-Dietz syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- multiple self-healing squamous epitheliomaInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -1 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_004612.4
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004612.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TGFBR1 | NM_004612.4 | MANE Select | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 9 | NP_004603.1 | P36897-1 | |
| TGFBR1 | NM_001306210.2 | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 9 | NP_001293139.1 | P36897-2 | ||
| TGFBR1 | NM_001407416.1 | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 8 | NP_001394345.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TGFBR1 | ENST00000374994.9 | TSL:1 MANE Select | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 9 | ENSP00000364133.4 | P36897-1 | |
| TGFBR1 | ENST00000552516.5 | TSL:1 | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 9 | ENSP00000447297.1 | P36897-2 | |
| TGFBR1 | ENST00000374990.6 | TSL:1 | c.64_78dupGCGGCGGCGGCGGCG | p.Ala22_Ala26dup | conservative_inframe_insertion | Exon 1 of 8 | ENSP00000364129.2 | P36897-3 |
Frequencies
GnomAD3 genomes 0.0000140 AC: 2AN: 142424Hom.: 0 Cov.: 30 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
142424
Hom.:
Cov.:
30
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000111 AC: 1AN: 900970Hom.: 0 Cov.: 7 AF XY: 0.00 AC XY: 0AN XY: 422764 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
900970
Hom.:
Cov.:
7
AF XY:
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:
AC:
0
AN:
17388
American (AMR)
AF:
AC:
0
AN:
2804
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
7300
East Asian (EAS)
AF:
AC:
0
AN:
9216
South Asian (SAS)
AF:
AC:
1
AN:
18064
European-Finnish (FIN)
AF:
AC:
0
AN:
5144
Middle Eastern (MID)
AF:
AC:
0
AN:
1952
European-Non Finnish (NFE)
AF:
AC:
0
AN:
807770
Other (OTH)
AF:
AC:
0
AN:
31332
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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 0.0000140 AC: 2AN: 142526Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 69400 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
2
AN:
142526
Hom.:
Cov.:
30
AF XY:
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:
AC:
1
AN:
39330
American (AMR)
AF:
AC:
1
AN:
14554
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3342
East Asian (EAS)
AF:
AC:
0
AN:
4824
South Asian (SAS)
AF:
AC:
0
AN:
4608
European-Finnish (FIN)
AF:
AC:
0
AN:
8144
Middle Eastern (MID)
AF:
AC:
0
AN:
266
European-Non Finnish (NFE)
AF:
AC:
0
AN:
64622
Other (OTH)
AF:
AC:
0
AN:
1984
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), 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:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
Familial thoracic aortic aneurysm and aortic dissection (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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