NM_000359.3:c.125C>A

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.125C>A(p.Ser42Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,880 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S42S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 34 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6O:1

Conservation

PhyloP100: 2.21

Publications

21 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=0.010242194).

BP6

Variant 14-24262228-G-T is Benign according to our data. Variant chr14-24262228-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12480.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00415 (632/152340) while in subpopulation NFE AF = 0.006 (408/68036). AF 95% confidence interval is 0.00552. There are 7 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.125C>A	p.Ser42Tyr	missense_variant	Exon 2 of 15	ENST00000206765.11	NP_000350.1	P22735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11 link	c.125C>A	p.Ser42Tyr	missense_variant	Exon 2 of 15	1	NM_000359.3	ENSP00000206765.6		P22735-1

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

632

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00600

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00427

AC:

1072

AN:

251102

AF XY:

0.00411

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00636

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00665

Gnomad NFE exome

AF:

0.00579

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00550

AC:

8039

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

3849

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33480

American (AMR)

AF:

0.00532

AC:

238

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00589

AC:

154

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00673

AC:

357

AN:

53072

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00618

AC:

6871

AN:

1112008

Other (OTH)

AF:

0.00586

AC:

354

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

535

1070

1605

2140

2675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00415

AC:

632

AN:

152340

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41568

American (AMR)

AF:

0.00464

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00668

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00600

AC:

408

AN:

68036

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00503

Hom.:

Bravo

AF:

0.00366

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:1Uncertain:1Benign:1Other:1

Jan 02, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 27, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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. -

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 01-16-2019 by Lab or GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -

not specified

Benign:3

Jan 02, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser42Tyr variant in TGM1 is classified as likely benign because it has been identified in 1.3% (4/316) of Middle Eastern and 0.67% (71/10628) of European Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is greater than the expected frequency of a pathogenic TGM1 variant causing disease. In addition, in vitro functional studies provide some evidence that this variant does not impact or increases protein expression (Candi 1998 PMID: 9593710, Numata 2016 PMID: 26990434). ACMG/AMP Criteria applied: BS1, BS3_Supporting. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2015

GeneDx

Significance:Likely 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. -

not provided

Benign:2

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGM1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T;T;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.52

M_CAP

Benign

0.045

MetaRNN

Benign

0.0099

T;T;T;T;T

MetaSVM

Uncertain

0.017

MutationAssessor

Benign

0.55

N;.;.;.;.

PhyloP100

2.2

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.33

N;N;D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.058

T;D;D;D;D

Sift4G

Uncertain

0.017

D;D;.;.;D

Polyphen

0.98

D;.;.;.;.

Vest4

0.54

MVP

0.97

MPC

0.81

ClinPred

0.011

GERP RS

4.7

Varity_R

0.14

gMVP

0.75

Mutation Taster

=265/35

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