rs771820315

chr14-24259721-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000359.3(TGM1):c.967C>T(p.Arg323Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,034 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. R323Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 0.894

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259720-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 14-24259721-G-A is Pathogenic according to our data. Variant chr14-24259721-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449108.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr14-24259721-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3	c.967C>T	p.Arg323Trp	missense_variant	6/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11	c.967C>T	p.Arg323Trp	missense_variant	6/15	1	NM_000359.3	P1
TGM1	ENST00000559136.1	c.40C>T	p.Arg14Trp	missense_variant	2/7	5
TGM1	ENST00000544573.5	c.-28-1333C>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245428 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133122

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: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459034 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725620

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: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGM1 related disorder (PMID:19241467). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012484, PMID:7824952,32573669). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.898>=0.6, 3CNET: 0.998>=0.75). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000163). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31168818, 31953843, 19241467, 23278109) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2023	This variant disrupts the p.Arg323 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824952, 9261103, 9545389, 23278109). 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. ClinVar contains an entry for this variant (Variation ID: 449108). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 19241467, 31168818, 31953843). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 323 of the TGM1 protein (p.Arg323Trp). For these reasons, this variant has been classified as Pathogenic. -

Lamellar ichthyosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 30, 2022

Variant summary: TGM1 c.967C>T (p.Arg323Trp) 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 1.6e-05 in 245428 control chromosomes (gnomAD). c.967C>T has been reported in the literature in individuals affected with Ichthyosis, including at least two cases where it has been found in trans with a pathogenic variant and one homozygous case (e.g. Herman_2009, Simpson_2020, Cheng_2020). These data indicate that the variant is likely to be associated with disease. This variant results in an amino acid change at the same position as another variant, c.968G>A (p.Arg323Gln), that has been classified as pathogenic with strong supporting evidence (ClinVar: 12484), suggesting this site may be important for normal protein function. To our knowledge, this has yet to be investigated by functional studies. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely pathogenic, one as pathogenic, and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.93		Loss of disorder (P = 0.0279);.;
MVP		0.99
MPC		0.94
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.83
gMVP		0.91

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

Other links and lift over

dbSNP: rs771820315; hg19: chr14-24728927;