rs142404759
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000359.3(TGM1):āc.1559A>Gā(p.Glu520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,614,004 control chromosomes in the GnomAD database, including 69 homozygotes. 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: š 0.0053 ( 5 hom., cov: 32)
Exomes š: 0.0083 ( 64 hom. )
Consequence
TGM1
NM_000359.3 missense
NM_000359.3 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 1.59
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0060895383).
BP6
?
Variant 14-24255450-T-C is Benign according to our data. Variant chr14-24255450-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr14-24255450-T-C is described in UniProt as null. Variant chr14-24255450-T-C is described in Lovd as [Pathogenic].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00534 (813/152118) while in subpopulation NFE AF= 0.00918 (624/67996). AF 95% confidence interval is 0.00858. There are 5 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.1559A>G | p.Glu520Gly | missense_variant | 11/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.1559A>G | p.Glu520Gly | missense_variant | 11/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000544573.5 | c.233A>G | p.Glu78Gly | missense_variant | 5/9 | 2 | |||
TGM1 | ENST00000559136.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00535 AC: 813AN: 152000Hom.: 5 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00571 AC: 1435AN: 251384Hom.: 5 AF XY: 0.00564 AC XY: 766AN XY: 135890
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GnomAD4 exome AF: 0.00826 AC: 12070AN: 1461886Hom.: 64 Cov.: 34 AF XY: 0.00809 AC XY: 5886AN XY: 727244
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GnomAD4 genome ? AF: 0.00534 AC: 813AN: 152118Hom.: 5 Cov.: 32 AF XY: 0.00523 AC XY: 389AN XY: 74360
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ExAC
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688
Asia WGS
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | TGM1: BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 23, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2019 | This variant is associated with the following publications: (PMID: 31642606, 27025581, 11348475, 21228398) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Autosomal recessive congenital ichthyosis 1 Uncertain:1Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 21, 2022 | - - |
TGM1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 16, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;D
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at