NM_000359.3:c.1559A>G

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.1559A>G(p.Glu520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,614,004 control chromosomes in the GnomAD database, including 69 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. E520K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 64 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.59

Publications

15 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=0.0060895383).

BP6

Variant 14-24255450-T-C is Benign according to our data. Variant chr14-24255450-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235714.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00534 (813/152118) while in subpopulation NFE AF = 0.00918 (624/67996). AF 95% confidence interval is 0.00858. There are 5 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.1559A>G	p.Glu520Gly	missense_variant	Exon 11 of 15	ENST00000206765.11	NP_000350.1	P22735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGM1	ENST00000206765.11 link	c.1559A>G	p.Glu520Gly	missense_variant	Exon 11 of 15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000544573.5 link	c.233A>G	p.Glu78Gly	missense_variant	Exon 5 of 9	2		ENSP00000439446.1	P22735-2
TGM1	ENST00000559136.1 link	c.*4A>G		downstream_gene_variant		5		ENSP00000453337.1	H0YLT9

Frequencies

GnomAD3 genomes

AF:

0.00535

AC:

813

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00623

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00918

Gnomad OTH

AF:

0.00624

GnomAD2 exomes

AF:

0.00571

AC:

1435

AN:

251384

AF XY:

0.00564

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00661

Gnomad NFE exome

AF:

0.00963

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00826

AC:

12070

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

5886

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00201

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00192

AC:

166

AN:

86258

European-Finnish (FIN)

AF:

0.00584

AC:

312

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00997

AC:

11090

AN:

1112010

Other (OTH)

AF:

0.00555

AC:

335

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

752

1504

2256

3008

3760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.00534

AC:

813

AN:

152118

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

389

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41484

American (AMR)

AF:

0.00249

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00623

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00918

AC:

624

AN:

67996

Other (OTH)

AF:

0.00618

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00818

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00567

AC:

688

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGM1: BP4, BS2 -

Jan 17, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31642606, 27025581, 11348475, 21228398) -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive congenital ichthyosis 1

Uncertain:1Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

May 21, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TGM1-related disorder

Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.63

M_CAP

Benign

0.060

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.90

L;.

PhyloP100

1.6

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.085

T;D

Sift4G

Benign

0.086

T;T

Polyphen

0.96

P;.

Vest4

0.21

MVP

0.93

MPC

0.98

ClinPred

0.036

GERP RS

5.4

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.34

gMVP

0.58

Mutation Taster

=77/23

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

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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