14-24258605-ATGTGT-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000359.3(TGM1):c.1223_1227delACACA(p.Asp408ValfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TGM1
NM_000359.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.02

Publications

6 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-24258605-ATGTGT-A is Pathogenic according to our data. Variant chr14-24258605-ATGTGT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24258605-ATGTGT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24258605-ATGTGT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24258605-ATGTGT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24258605-ATGTGT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.1223_1227delACACA	p.Asp408ValfsTer21	frameshift_variant	Exon 8 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.1223_1227delACACA	p.Asp408ValfsTer21	frameshift_variant	Exon 8 of 15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000559136.1 link	c.296_300delACACA	p.Asp99ValfsTer21	frameshift_variant	Exon 4 of 7	5		ENSP00000453337.1	H0YLT9
TGM1	ENST00000544573.5 link	c.-28-222_-28-218delACACA		intron_variant	Intron 2 of 8	2		ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251410

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461894

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112012

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:6

Nov 08, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TGM1 c.1223_1227delACACA (p.Asp408ValfsTer21) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Asp408ValfsTer21 variant has been reported in four studies in which it is found in a total of eight patients with congenital ichthyosis, including in three in a homozygous state and in five in a compound heterozygous state with the same stop-gained variant on the second allele (Herman et al. 2009; RodrÃguez-Pazos et al. 2011; Fachal et al. 2012; Esposito et al. 2013). Facal et al. (2012) report the variant to be present in 21% of disease alleles in the Galician region of Spain. Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.Asp408ValfsTer21 variant is classified as likely pathogenic for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asp408Valfs*21) in the TGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGM1 are known to be pathogenic (PMID: 18948357, 19241467). This variant is present in population databases (rs398122905, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 19241467, 21668430, 22511925, 23278109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 39537). For these reasons, this variant has been classified as Pathogenic. -

Jun 22, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22511925, 21668430, 19241467, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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