rs1555755242
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM1PM2PP5_Moderate
The NM_000660.7(TGFB1):c.328C>T(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Genomes: not found (cov: 31)
Consequence
TGFB1
NM_000660.7 missense
NM_000660.7 missense
Scores
4
8
5
Clinical Significance
Conservation
PhyloP100: 1.37
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 made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PS1
?
Transcript NM_000660.7 (TGFB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_000660.7
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-41352717-G-A is Pathogenic according to our data. Variant chr19-41352717-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488345.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB1 | NM_000660.7 | c.328C>T | p.Arg110Cys | missense_variant | 1/7 | ENST00000221930.6 | |
TGFB1 | XM_011527242.3 | c.328C>T | p.Arg110Cys | missense_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB1 | ENST00000221930.6 | c.328C>T | p.Arg110Cys | missense_variant | 1/7 | 1 | NM_000660.7 | P1 | |
TMEM91 | ENST00000539627.5 | c.-30+1515G>A | intron_variant | 1 | |||||
TGFB1 | ENST00000600196.2 | c.328C>T | p.Arg110Cys | missense_variant | 1/6 | 5 | |||
TGFB1 | ENST00000677934.1 | c.328C>T | p.Arg110Cys | missense_variant | 1/5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inflammatory bowel disease, immunodeficiency, and encephalopathy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 04, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Feb 27, 2019 | This variant is interpreted as a Likely pathogenic for Inflammatory bowel disease, immunodeficiency, and encephalopathy, autosomal recessive. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate : PS3 downgraded in strength to Moderate (PMID:29483653). PM3 : For recessive disorders, detected in trans with a pathogenic variant (PMID:29483653). - |
Encephalopathy;C4749850:Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | Klein lab, Ludwig-Maximilians-University | Jan 01, 2017 | Variant is associated with primary immunodeficiency, inflammatory bowel disease and encephalopathy. Variant was found in compound heterozygosity with another variant in TGFB1 (c.1159T>C). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of catalytic residue at E107 (P = 0.0727);
MVP
MPC
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