rs112292549

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4

The NM_201631.4(TGM5):​c.337G>T​(p.Gly113Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,614,140 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

TGM5
NM_201631.4 missense

Scores

13
3
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.73
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 15-43260151-C-A is Pathogenic according to our data. Variant chr15-43260151-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43260151-C-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.10193285). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGM5NM_201631.4 linkc.337G>T p.Gly113Cys missense_variant Exon 3 of 13 ENST00000220420.10 NP_963925.2 O43548-1B4DPS8
TGM5NM_004245.4 linkc.190+249G>T intron_variant Intron 2 of 11 NP_004236.1 O43548-2B4DPS8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGM5ENST00000220420.10 linkc.337G>T p.Gly113Cys missense_variant Exon 3 of 13 1 NM_201631.4 ENSP00000220420.5 O43548-1
TGM5ENST00000349114.8 linkc.190+249G>T intron_variant Intron 2 of 11 1 ENSP00000220419.8 O43548-2

Frequencies

GnomAD3 genomes
AF:
0.00242
AC:
369
AN:
152176
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00222
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00165
Gnomad FIN
AF:
0.00396
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00370
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00235
AC:
589
AN:
251022
Hom.:
2
AF XY:
0.00247
AC XY:
335
AN XY:
135830
show subpopulations
Gnomad AFR exome
AF:
0.000744
Gnomad AMR exome
AF:
0.000549
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00150
Gnomad FIN exome
AF:
0.00352
Gnomad NFE exome
AF:
0.00356
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.00286
AC:
4181
AN:
1461846
Hom.:
13
Cov.:
32
AF XY:
0.00281
AC XY:
2043
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.00138
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00134
Gnomad4 FIN exome
AF:
0.00288
Gnomad4 NFE exome
AF:
0.00332
Gnomad4 OTH exome
AF:
0.00230
GnomAD4 genome
AF:
0.00242
AC:
369
AN:
152294
Hom.:
1
Cov.:
31
AF XY:
0.00251
AC XY:
187
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00396
Gnomad4 NFE
AF:
0.00370
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00305
Hom.:
1
Bravo
AF:
0.00202
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00454
AC:
39
ExAC
AF:
0.00259
AC:
314
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00365
EpiControl
AF:
0.00279

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Acral peeling skin syndrome Pathogenic:8Other:1
Oct 07, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3_strong, PS3, PP1, PP3 -

Oct 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 18, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Across a selection of the available literature, the TGM5 c.337G>T (p.Gly113Cys) missense variant, which is a founder variant in the European population, was reported in at least 97 patients, including in a homozygous state in at least 91 patients with peeling skin syndrome, in a compound heterozygous state in at least six patients, and in a heterozygous state in six unaffected parents of patients (Cassidy et al. 2005; Kiritsi et al. 2010; van der Velden et al. 2012; Pigors et al. 2012; Kavaklieva et al. 2013; Szczecinska et al. 2014; Kopečková et al. 2016). The variant was identified in a heterozygous state in four out of 250 controls and is reported at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. This frequency is higher than expected based on disease prevalence estimates, but may be consistent with under-diagnosis and with the fact that this is a common founder variant. Cassidy et al. (2005) measured enzyme activity for the p.Gly113Cys variant in two different epithelial cell lines and demonstrated that the variant completely abolished activity. Based on the collective evidence, the p.Gly113Cys variant is classified as pathogenic for peeling skin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 19, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 17, 2023
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with peeling skin syndrome 2 (MIM#609796). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (657 heterozygotes, 2 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated N-terminal transglutaminase domain (NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous and compound heterozygous in individuals with peeling skin syndrome (ClinVar, PMID: 29242947). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cell lines displayed complete loss of enzyme activity (PMID: 16380904). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 08, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3_SUP,PP3 -

not provided Pathogenic:4
Jun 22, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 08, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Common variant identified especially in individuals of Northern European descent (Lek et al., 2016); Published functional studies demonstrate that G113C completely abolishes cross-linking activity of the enzyme in transfected epithelial cell lines (Cassidy et al., 2005; van der Velden et al., 2015); This variant is associated with the following publications: (PMID: 16380904, 24019772, 27206604, 26707537, 30688214, 31028847, 20301543, 20220177, 19440220, 22622422, 25510201, 26684698, 22429841, 24628291, 29242947, 31001817, 31980526, 25644735, 20164844, 31589614) -

Jun 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TGM5: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -

Oct 17, 2022
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3, PS3, PP4, PP3, PS4 -

Inborn genetic diseases Pathogenic:1
Oct 03, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

TGM5-related disorder Pathogenic:1
Jun 09, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The TGM5 c.337G>T variant is predicted to result in the amino acid substitution p.Gly113Cys. This variant, in either the homozygous or compound heterozygous states with a second pathogenic variant, has been reported to be causative for acral peeling skin syndrome in multiple unrelated families (Cassidy et al. 2005. PubMed ID: 16380904; Kiritsi et al. 2010. PubMed ID: 20164844; Pigors et al. 2012. PubMed ID: 22622422; Kavaklieva et al. 2013. PubMed ID: 24019772; van der Velden et al 2015. PubMed ID: 25644735; Has et al. 2018. PubMed ID: 29242947). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
D;D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Pathogenic
0.55
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.7
.;H;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-8.4
.;D;.
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.98
MVP
0.75
MPC
0.66
ClinPred
0.15
T
GERP RS
5.3
Varity_R
0.96
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs112292549; hg19: chr15-43552349; COSMIC: COSV105015799; API