rs863223405
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000359.3(TGM1):c.1363T>C(p.Trp455Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
TGM1
NM_000359.3 missense
NM_000359.3 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 7.50
Genes affected
TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 14-24258324-A-G is Pathogenic according to our data. Variant chr14-24258324-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217304.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.1363T>C | p.Trp455Arg | missense_variant | 9/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.1363T>C | p.Trp455Arg | missense_variant | 9/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000544573.5 | c.37T>C | p.Trp13Arg | missense_variant | 3/9 | 2 | |||
TGM1 | ENST00000559136.1 | c.436T>C | p.Trp146Arg | missense_variant | 5/7 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:2
Pathogenic, no assertion criteria provided | research | Department of Molecular and Human Genetics, Baylor College of Medicine | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | May 20, 2020 | A homozygous missense variation in exon 9 of the TGM1 gene that results in the amino acid substitution of Arginine for Tryptophan at codon 455 was detected. The observed variant c.1363T>C (p.Trp455Arg) has not been reported in the 1000 genomes and ExAC databases. The observed variation lies in the transglutaminase-like superfamily domain of the TGM1 protein and has previously been reported in patients affected with congenital ichthyosis (Ullah, Rahim et al. 2016). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. - |
Ichthyosis Pathogenic:1
Pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Nov 17, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;.
Polyphen
D;.;.
Vest4
MutPred
Gain of disorder (P = 0.0094);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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