rs113463533

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 16/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.540

Publications

12 publications found

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]

TGM5 Gene-Disease associations (from GenCC):

acral peeling skin syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P

TGM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TGM5	NM_201631.4 link	c.326C>T	p.Thr109Met	missense_variant	Exon 3 of 13	ENST00000220420.10	NP_963925.2	O43548-1B4DPS8
TGM5	NM_004245.4 link	c.190+238C>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
TGM5	ENST00000220420.10 link	c.326C>T	p.Thr109Met	missense_variant	Exon 3 of 13	1	NM_201631.4	ENSP00000220420.5		O43548-1
TGM5	ENST00000349114.8 link	c.190+238C>T		intron_variant	Intron 2 of 11	1		ENSP00000220419.8		O43548-2

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

950

AN:

152200

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00986

AC:

2476

AN:

251234

AF XY:

0.00939

show subpopulations

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 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.:

AF XY:

0.00589

AC XY:

4282

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33478

American (AMR)

AF:

0.00514

AC:

230

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00245

AC:

AN:

26136

East Asian (EAS)

AF:

0.0817

AC:

3242

AN:

39700

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86258

European-Finnish (FIN)

AF:

0.00328

AC:

175

AN:

53356

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00395

AC:

4392

AN:

1112012

Other (OTH)

AF:

0.00662

AC:

400

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

583

1165

1748

2330

2913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00624

AC:

950

AN:

152318

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

491

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41588

American (AMR)

AF:

0.00562

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.0853

AC:

442

AN:

5180

South Asian (SAS)

AF:

0.00497

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00425

AC:

289

AN:

68010

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00649

Hom.:

Bravo

AF:

0.00604

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00512

AC:

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:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Acral peeling skin syndrome

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.5

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.029

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.32

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.23

.;N;.

PhyloP100

-0.54

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.5

.;N;.

REVEL

Benign

0.13

Sift

Benign

0.23

.;T;.

Sift4G

Benign

0.20

T;T;T

Polyphen

0.015

.;B;.

Vest4

0.15

MVP

0.27

MPC

0.16

ClinPred

0.0011

GERP RS

-5.0

Varity_R

0.033

gMVP

0.28

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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rs113463533

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over