rs202037016

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_000359.3(TGM1):c.1075G>A(p.Val359Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V359V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 2.61

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000359.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

PP5

Variant 14-24259159-C-T is Pathogenic according to our data. Variant chr14-24259159-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39532.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr14-24259159-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.1075G>A	p.Val359Met	missense_variant	7/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.1075G>A	p.Val359Met	missense_variant	7/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000559136.1 linkuse as main transcript	c.148G>A	p.Val50Met	missense_variant	3/7	5
TGM1	ENST00000544573.5 linkuse as main transcript	c.-28-771G>A		intron_variant		2			P22735-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251160

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000183

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 03, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2009	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 359 of the TGM1 protein (p.Val359Met). This variant is present in population databases (rs202037016, gnomAD 0.0009%). This missense change has been observed in individuals with congenital ichthyosis ( (PMID: 19241467, 19500103). ClinVar contains an entry for this variant (Variation ID: 39532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGM1 protein function. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19500103). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 03, 2023

Variant summary: TGM1 c.1075G>A (p.Val359Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251160 control chromosomes. c.1075G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with features of Autosomal recessive congenital ichthyosis (ARCI) or a novel phenotype of acral self-healing collodion baby (example, Herman_2009, Mazereeuw-Hautier_2009). The case report describing the novel phenotype of acral self-healing collodion baby reports its presence in a family with three segregating variants in the TGM1 gene (Mazereeuw-Hautier_2009). The proband was compound heterozygous for this paternally inherited variant and a maternally inherited p.Arg396His variant. While the sister was compound heterozygous for a different paternally inherited variant (c.1922_1926+2delGGCCTGT) and maternally inherited p.Arg396His variant seen in her proband sibling. The father who carries the deletion and the p.Val359Met mutation was reported as having no clinical symptoms, although the authors did not rule out the possibility that he was not aware of a very transient and mild anomaly of his skin at birth.. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Mazereeuw-Hautier_2009). The most pronounced variant effect results in 12.8% of normal recombinant transglutaminase enzyme activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 19241467, 19500103). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Both labs cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;.

Polyphen

1.0

D;.

Vest4

0.83

MVP

0.94

MPC

0.92

ClinPred

0.89

GERP RS

4.3

Varity_R

0.49

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over