rs398122901

Variant names:

• chr14-24262048-T-A
• rs398122901
• NM_000359.3:c.305A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-24262048-T-A
• chr14-24262048-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_000359.3(TGM1):​c.305A>T​(p.Asp102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. D102D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.42
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 14-24262048-T-A is Pathogenic according to our data. Variant chr14-24262048-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39525.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.305A>T	p.Asp102Val	missense_variant	Exon 2 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.305A>T	p.Asp102Val	missense_variant	Exon 2 of 15	1	NM_000359.3	ENSP00000206765.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:1

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		1.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.23	N;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.090	T;T
Polyphen		0.72	P;.
Vest4		0.89
MutPred		0.75		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.97
MPC		0.67
ClinPred		0.68	D
GERP RS		3.5
Varity_R		0.15
gMVP		0.74
Mutation Taster		=35/65	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: rs398122901; hg19: chr14-24731254;