chr14-24259959-C-T

Variant names:

• chr14-24259959-C-T
• rs121918727
• NM_000359.3:c.857G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000359.3(TGM1):​c.857G>A​(p.Arg286Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,852 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R286W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.70
• Publications: 7 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 0 uncertain in NM_000359.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259960-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 633786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 81 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: -0.060191 (below the threshold of 3.09). Trascript score misZ: 1.7514 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 1, acral self-healing collodion baby, bathing suit ichthyosis, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis, self-healing collodion baby.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 14-24259959-C-T is Pathogenic according to our data. Variant chr14-24259959-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000359.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.857G>A	p.Arg286Gln	missense	Exon 5 of 15	NP_000350.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.857G>A	p.Arg286Gln	missense	Exon 5 of 15	ENSP00000206765.6
	TGM1	ENST00000559136.1	TSL:5	c.-71G>A		5_prime_UTR	Exon 1 of 7	ENSP00000453337.1
	TGM1	ENST00000544573.5	TSL:2	c.-28-1571G>A		intron	N/A	ENSP00000439446.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251400 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 727230

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000141 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:4

Sep 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Dec 14, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R286Q pathogenic variant in the TGM1 gene has been reported previously with another TGM1 variant in an individual with lamellar ichthyosis (Cserhalmi-Friedman et al., 2001). R286Q has also been observed with another pathogenic variant or in the apparent homozygous state in several unrelated patients with congenital ichthyosis referred for genetic testing at GeneDx. The R286Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R286Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R286Q as a pathogenic variant.

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 286 of the TGM1 protein (p.Arg286Gln). This variant is present in population databases (rs121918727, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 11298529, 28403434, 31168818). ClinVar contains an entry for this variant (Variation ID: 12495). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGM1 protein function. This variant disrupts the p.Arg286 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been observed in individuals with TGM1-related conditions (PMID: 30578701), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

TGM1-related disorder Pathogenic:1

Feb 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TGM1 c.857G>A variant is predicted to result in the amino acid substitution p.Arg286Gln. This variant was reported in an individual with lamellar ichthyosis (Cserhalmi-Friedman et al. 2001. PubMed ID: 11298529; Marukian et al. 2017. PubMed ID: 28403434; Simpson et al. 2019. PubMed ID: 31168818). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Of note, another missense variant, affecting the same amino acid (p.Arg286Trp), has also been reported to be causative for lamellar ichthyosis (Youssefian et al. 2019. PubMed ID: 30578701). This variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.36	N
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.78		Gain of sheet (P = 0.1208)
MVP		0.98
MPC		0.99
ClinPred		0.90	D
GERP RS		5.4
PromoterAI		-0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.78
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121918727; hg19: chr14-24729165; COSMIC: COSV52861826; COSMIC: COSV52861826;