rs113463533

chr15-43260162-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201631.4(TGM5):c.326C>T(p.Thr109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,614,134 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (19 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (159 hom.)
• Consequence: TGM5 NM_201631.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.540

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024375916).
• BP6: Variant 15-43260162-G-A is Benign according to our data. Variant chr15-43260162-G-A is described in ClinVar as [Benign]. Clinvar id is 137639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM5	NM_201631.4	c.326C>T	p.Thr109Met	missense_variant	3/13	ENST00000220420.10
TGM5	NM_004245.4	c.190+238C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM5	ENST00000220420.10	c.326C>T	p.Thr109Met	missense_variant	3/13	1	NM_201631.4	P1
TGM5	ENST00000349114.8	c.190+238C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152200 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0853

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00986 AC: 2476 AN: 251234 Hom.: 63 AF XY: 0.00939 AC XY: 1276 AN XY: 135862

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0856

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.00385

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00600 AC: 8770 AN: 1461816 Hom.: 159 Cov.: 32 AF XY: 0.00589 AC XY: 4282 AN XY: 727214

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00514

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0817

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00395

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152318 Hom.: 19 Cov.: 31 AF XY: 0.00659 AC XY: 491 AN XY: 74476

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0853

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.00425

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00641 Hom.: 21

Bravo AF: 0.00604

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00326

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acral peeling skin syndrome Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.5
Dann	Benign	0.93
DEOGEN2	Benign	0.029	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.32	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.015	.;B;.
Vest4		0.15
MVP		0.27
MPC		0.16
ClinPred		0.0011	T
GERP RS		-5.0
Varity_R		0.033
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs113463533; hg19: chr15-43552360; COSMIC: COSV55010176;