rs121918727

Positions:

• chr14-24259959-C-A
• chr14-24259959-C-G
• chr14-24259959-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The ENST00000206765.11(TGM1):​c.857G>T​(p.Arg286Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R286Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGM1 ENST00000206765.11 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259959-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 14-24259959-C-A is Pathogenic according to our data. Variant chr14-24259959-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1469208.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3	c.857G>T	p.Arg286Leu	missense_variant	5/15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.857G>T	p.Arg286Leu	missense_variant	5/15	1	NM_000359.3	ENSP00000206765	P1
TGM1	ENST00000559136.1	c.-71G>T		5_prime_UTR_variant	1/7	5		ENSP00000453337
TGM1	ENST00000544573.5	c.-28-1571G>T		intron_variant		2		ENSP00000439446

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2021

This sequence change replaces arginine with leucine at codon 286 of the TGM1 protein (p.Arg286Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the p.Arg286 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11298529, 28403434, 31168818). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with TGM1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.38	N
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.58		Loss of disorder (P = 0.149);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24729165;