14-24255457-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000359.3(TGM1):c.1552G>A(p.Val518Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,614,116 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V518L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 33)

Exomes 𝑓: 0.016 ( 212 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:10

Conservation

PhyloP100: 0.624

Publications

22 publications found

Variant links:

Genes affected

TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]

TGM1 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, Genomics England PanelApp
acral self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
bathing suit ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TGM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 81 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: -0.060191 (below the threshold of 3.09). Trascript score misZ: 1.7514 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 1, acral self-healing collodion baby, bathing suit ichthyosis, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis, self-healing collodion baby.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077917576).

BP6

Variant 14-24255457-C-T is Benign according to our data. Variant chr14-24255457-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12496.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1661/152256) while in subpopulation NFE AF = 0.0185 (1261/68014). AF 95% confidence interval is 0.0177. There are 18 homozygotes in GnomAd4. There are 771 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.1552G>A	p.Val518Met	missense_variant	Exon 11 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TGM1	ENST00000206765.11 link	c.1552G>A	p.Val518Met	missense_variant	Exon 11 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5 link	c.226G>A	p.Val76Met	missense_variant	Exon 5 of 9	2		ENSP00000439446.1
TGM1	ENST00000559136.1 link	c.625G>A	p.Val209Met	missense_variant	Exon 7 of 7	5		ENSP00000453337.1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1661

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.0107

AC:

2691

AN:

251390

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00585

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0164

AC:

23995

AN:

1461860

Hom.:

212

Cov.:

AF XY:

0.0162

AC XY:

11748

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33474

American (AMR)

AF:

0.00248

AC:

111

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

166

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00325

AC:

280

AN:

86256

European-Finnish (FIN)

AF:

0.0157

AC:

836

AN:

53418

Middle Eastern (MID)

AF:

0.00348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0195

AC:

21641

AN:

1112010

Other (OTH)

AF:

0.0143

AC:

861

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1535

3071

4606

6142

7677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1661

AN:

152256

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

771

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00335

AC:

139

AN:

41546

American (AMR)

AF:

0.00340

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0151

AC:

160

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1261

AN:

68014

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

175

262

350

437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.00953

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0104

AC:

1264

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0152

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:1Uncertain:1Benign:3

Apr 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The p.Val518Met variant in TGM1 has been identified in at least 2 individuals with lamellar ichthyosis (PMID: 9545389), and has been identified in >1% of Euroopean (Finnish) chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for lamellar ichthyosis. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGM1: BP4, BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.20

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

0.62

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.065

T;T;D

Sift4G

Benign

0.073

T;D;.

Polyphen

0.98

D;.;.

Vest4

0.17

MPC

0.83

ClinPred

0.019

GERP RS

4.9

PromoterAI

-0.0078

Neutral

(source)

Varity_R

0.15

gMVP

0.36

Mutation Taster

=90/10

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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