rs771820315

Variant names:

• chr14-24259721-G-A
• rs771820315
• NM_000359.3:c.967C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-24259721-G-A
• chr14-24259721-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★). 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 0.894
• Publications: 4 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 19 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, 7 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.
• 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, 0.981
• PP5: Variant 14-24259721-G-A is Pathogenic according to our data. Variant chr14-24259721-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.967C>T	p.Arg323Trp	missense_variant	Exon 6 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.967C>T	p.Arg323Trp	missense_variant	Exon 6 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000559136.1	c.40C>T	p.Arg14Trp	missense_variant	Exon 2 of 7	5		ENSP00000453337.1
TGM1	ENST00000544573.5	c.-28-1333C>T		intron_variant	Intron 2 of 8	2		ENSP00000439446.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 245428 AF XY: 0.0000150

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110960

Other (OTH) AF: 0.0000166 AC: 1 AN: 60278

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:3 Uncertain:1

Feb 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:2

Aug 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 449108). For these reasons, this variant has been classified as Pathogenic. 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. 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). -

Apr 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Lamellar ichthyosis Pathogenic:1

Jun 30, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		0.89
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
PromoterAI		0.022	Neutral
Varity_R		0.83
gMVP		0.91
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs771820315; hg19: chr14-24728927;