GeneBe

9-99105193-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004612.4(TGFBR1):​c.-13T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,071,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

TGFBR1
NM_004612.4 5_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.877

Publications

0 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: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BS1
Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000303 (282/929458) while in subpopulation NFE AF = 0.000323 (266/824142). AF 95% confidence interval is 0.00029. There are 0 homozygotes in GnomAdExome4. There are 129 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR1NM_004612.4 linkc.-13T>C 5_prime_UTR_variant 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.-13T>C 5_prime_UTR_variant Exon 1 of 9 1 NM_004612.4 ENSP00000364133.4 P36897-1

Frequencies

GnomAD3 genomes
AF:
0.000190
AC:
27
AN:
142470
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000262
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:
0.000399
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000303
AC:
282
AN:
929458
Hom.:
0
Cov.:
30
AF XY:
0.000297
AC XY:
129
AN XY:
434518
show subpopulations
African (AFR)
AF:
0.000217
AC:
4
AN:
18462
American (AMR)
AF:
0.00
AC:
0
AN:
3546
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
8886
East Asian (EAS)
AF:
0.00
AC:
0
AN:
12956
South Asian (SAS)
AF:
0.000110
AC:
2
AN:
18208
European-Finnish (FIN)
AF:
0.000132
AC:
1
AN:
7556
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2150
European-Non Finnish (NFE)
AF:
0.000323
AC:
266
AN:
824142
Other (OTH)
AF:
0.000268
AC:
9
AN:
33552
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
17
34
51
68
85
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.000190
AC:
27
AN:
142470
Hom.:
0
Cov.:
32
AF XY:
0.000130
AC XY:
9
AN XY:
69440
show subpopulations
African (AFR)
AF:
0.0000262
AC:
1
AN:
38234
American (AMR)
AF:
0.00
AC:
0
AN:
14594
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3388
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4734
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4452
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8782
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
278
European-Non Finnish (NFE)
AF:
0.000399
AC:
26
AN:
65164
Other (OTH)
AF:
0.00
AC:
0
AN:
1974
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000162

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Uncertain:1
Oct 19, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Loeys-Dietz syndrome 1 Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Loeys-Dietz syndrome Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Sep 30, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: TGFBR1 c.-13T>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0003 in 929458 control chromosomes. The observed variant frequency is approximately 161.81 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06). To our knowledge, no occurrence of c.-13T>C in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 364096). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.64
CADD
Benign
15
DANN
Benign
0.88
PhyloP100
-0.88
PromoterAI
-0.034
Neutral
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
3.3
Mutation Taster
=300/0
polymorphism

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

Other links and lift over

dbSNP: rs886063220; hg19: chr9-101867475; API