rs111033611
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000660.7(TGFB1):c.241T>C(p.Tyr81His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y81C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
TGFB1
NM_000660.7 missense
NM_000660.7 missense
Scores
10
6
Clinical Significance
Conservation
PhyloP100: 7.19
Publications
19 publications found
Genes affected
TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]
TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PM1
In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000660.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 19-41352804-A-G is Pathogenic according to our data. Variant chr19-41352804-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12532.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TGFB1 | ENST00000221930.6 | c.241T>C | p.Tyr81His | missense_variant | Exon 1 of 7 | 1 | NM_000660.7 | ENSP00000221930.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455512Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 723482 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1455512
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
723482
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33336
American (AMR)
AF:
AC:
0
AN:
43952
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25904
East Asian (EAS)
AF:
AC:
0
AN:
39482
South Asian (SAS)
AF:
AC:
0
AN:
85628
European-Finnish (FIN)
AF:
AC:
0
AN:
52388
Middle Eastern (MID)
AF:
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1109000
Other (OTH)
AF:
AC:
0
AN:
60074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
31
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Diaphyseal dysplasia Pathogenic:1Other:1
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
Nov 01, 2000
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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