rs112292549

Positions:

• chr15-43260151-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.73

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]

ACMG classification

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/exons	MANE	Protein	UniProt
TGM5	NM_201631.4	c.337G>T	p.Gly113Cys	missense_variant	3/13	ENST00000220420.10	NP_963925.2
TGM5	NM_004245.4	c.190+249G>T		intron_variant			NP_004236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM5	ENST00000220420.10	c.337G>T	p.Gly113Cys	missense_variant	3/13	1	NM_201631.4	ENSP00000220420	P1
TGM5	ENST00000349114.8	c.190+249G>T		intron_variant		1		ENSP00000220419

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152176 Hom.: 1 Cov.: 31

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

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

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

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acral peeling skin syndrome Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 08, 2024	Criteria applied: PM3_VSTR,PS3_SUP,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 01, 2021	PM3_strong, PS3, PP1, PP3 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 07, 2021	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Oct 17, 2022	PM3, PS3, PP4, PP3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TGM5: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	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) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2016

- -

TGM5-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2023

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;.
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

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