9-99105175-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_004612.4(TGFBR1):​c.-31G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,088,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000063 ( 1 hom. )

Consequence

TGFBR1
NM_004612.4 5_prime_UTR

Scores

1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.172

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 -7 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000468 (7/149502) while in subpopulation EAS AF = 0.00118 (6/5104). AF 95% confidence interval is 0.000512. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR1NM_004612.4 linkc.-31G>A 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.-31G>A 5_prime_UTR_variant Exon 1 of 9 1 NM_004612.4 ENSP00000364133.4 P36897-1

Frequencies

GnomAD3 genomes
AF:
0.0000469
AC:
7
AN:
149394
Hom.:
0
Cov.:
32
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:
0.00117
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000628
AC:
59
AN:
938788
Hom.:
1
Cov.:
30
AF XY:
0.0000570
AC XY:
25
AN XY:
438566
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
18758
American (AMR)
AF:
0.00
AC:
0
AN:
3850
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
9338
East Asian (EAS)
AF:
0.00414
AC:
58
AN:
14010
South Asian (SAS)
AF:
0.0000547
AC:
1
AN:
18280
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2196
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
829468
Other (OTH)
AF:
0.00
AC:
0
AN:
34300
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.534
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
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:
0.0000468
AC:
7
AN:
149502
Hom.:
0
Cov.:
32
AF XY:
0.0000548
AC XY:
4
AN XY:
73016
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41196
American (AMR)
AF:
0.00
AC:
0
AN:
15052
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3436
East Asian (EAS)
AF:
0.00118
AC:
6
AN:
5104
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4810
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9580
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
286
European-Non Finnish (NFE)
AF:
0.0000149
AC:
1
AN:
67048
Other (OTH)
AF:
0.00
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Loeys-Dietz syndrome 1 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
18
DANN
Uncertain
0.97
PhyloP100
0.17
PromoterAI
0.12
Neutral
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
3.6
Mutation Taster
=299/1
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: rs1404137226; hg19: chr9-101867457; API