rs121918724

Positions:

chr14-24256011-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000359.3(TGM1):c.1469A>G(p.Asp490Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000575 in 1,566,280 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. D490N) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.82

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 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24256012-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2899841.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 14-24256011-T-C is Pathogenic according to our data. Variant chr14-24256011-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12491.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr14-24256011-T-C is described in UniProt as null. Variant chr14-24256011-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.1469A>G	p.Asp490Gly	missense_variant	10/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.1469A>G	p.Asp490Gly	missense_variant	10/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000544573.5 linkuse as main transcript	c.143A>G	p.Asp48Gly	missense_variant	4/9	2			P22735-2
TGM1	ENST00000559136.1 linkuse as main transcript	c.542A>G	p.Asp181Gly	missense_variant	6/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000613

AC:

AN:

179310

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

95220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000291

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000594

AC:

AN:

1414174

Hom.:

Cov.:

AF XY:

0.0000859

AC XY:

AN XY:

698700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000224

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000552

Gnomad4 OTH exome

AF:

0.0000853

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000589

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:3Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2017	- -

Lamellar ichthyosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 03, 2023

Variant summary: TGM1 c.1469A>G (p.Asp490Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 179310 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (6.1e-05 vs 0.0021), allowing no conclusion about variant significance. c.1469A>G has been reported in the literature in two compound heterozygous siblings affected with self-healing collodion baby (SHCB), which is a milder condition related to Lamellar Ichthyosis (Raghunath_2003), where both patients carried a (likely) pathogenic variant in trans. This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced TGase I activity under elevated hydrostatic pressure (Raghunath_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after, and classified the variant as pathogenic (n=1), and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 490 of the TGM1 protein (p.Asp490Gly). This variant is present in population databases (rs121918724, gnomAD 0.03%). This missense change has been observed in individual(s) with spontaneous healing of congenital ichthyosis (PMID: 12542526). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12491). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 12542526). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.93

MVP

0.99

MPC

1.1

ClinPred

0.95

GERP RS

5.1

Varity_R

0.92

gMVP

0.95

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