rs1465243895

Variant names:

Variant summary

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

The NM_000359.3(TGM1):c.431G>A(p.Gly144Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G144R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.56

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 chr14-24261773-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 14-24261772-C-T is Pathogenic according to our data. Variant chr14-24261772-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555239.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr14-24261772-C-T is described in UniProt as null. Variant chr14-24261772-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.431G>A	p.Gly144Glu	missense_variant	Exon 3 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.431G>A	p.Gly144Glu	missense_variant	Exon 3 of 15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000544573.5 link	c.-29+355G>A		intron_variant	Intron 2 of 8	2		ENSP00000439446.1	P22735-2
TGM1	ENST00000558074.1 link	c.*26G>A		downstream_gene_variant		5		ENSP00000453840.1	H0YN27

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:1Uncertain:1

Nov 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lamellar ichthyosis

Pathogenic:1

Jun 20, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGM1 c.431G>A (p.Gly144Glu) results in a non-conservative amino acid change located in the immunoglobulin-like fold domain (IPR013783) of 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 8e-06 in 251454 control chromosomes. c.431G>A has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with Lamellar Ichthyosis (e.g. Petit_1997, Esposito_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro. The most pronounced variant effect results in <10% of normal activity (e.g. Petit_1997). The following publications have been ascertained in the context of this evaluation (PMID: 23278109, 9359043). ClinVar contains an entry for this variant (Variation ID: 555239). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.97

MutPred

0.99

Gain of disorder (P = 0.0682);

MVP

0.99

MPC

1.1

ClinPred

0.99

GERP RS

4.2

Varity_R

0.94

gMVP

0.92

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

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