chr15-43260486-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_201631.4(TGM5):c.104G>A(p.Arg35Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,614,032 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 (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
TGM5
NM_201631.4 missense
NM_201631.4 missense
Scores
9
3
3
Clinical Significance
Conservation
PhyloP100: 5.52
Genes affected
TGM5 (HGNC:11781): (transglutaminase 5) This gene encodes a member of the transglutaminase family. The encoded protein catalyzes formation of protein cross-links between glutamine and lysine residues, often resulting in stabilization of protein assemblies. This reaction is calcium dependent. Mutations in this gene have been associated with acral peeling skin syndrome. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916
PP5
Variant 15-43260486-C-T is Pathogenic according to our data. Variant chr15-43260486-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 449109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43260486-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM5 | NM_201631.4 | c.104G>A | p.Arg35Gln | missense_variant | 2/13 | ENST00000220420.10 | |
TGM5 | NM_004245.4 | c.104G>A | p.Arg35Gln | missense_variant | 2/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM5 | ENST00000220420.10 | c.104G>A | p.Arg35Gln | missense_variant | 2/13 | 1 | NM_201631.4 | P1 | |
TGM5 | ENST00000349114.8 | c.104G>A | p.Arg35Gln | missense_variant | 2/12 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251478Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135912
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GnomAD4 exome AF: 0.0000876 AC: 128AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66AN XY: 727246
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74332
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2023 | Identified with a second variant in additional patients with acral peeling skin syndrome referred for genetic testing at GeneDx and in published literature (PMID: 24628291); Published functional studies demonstrate a complete loss of cross-linking activity of the enzyme in transfected epithelial cell lines (PMID: 25644735); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 24628291, 25644735) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;T;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;N
PrimateAI
Benign
T
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
1.0
.;.;D;.;D
Vest4
0.92, 0.65
MVP
MPC
0.69
ClinPred
D
GERP RS
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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