rs878853259

Variant names:

• chr14-24260593-A-T
• rs878853259
• NM_000359.3:c.614T>A
• TGM1 p.Leu205Gln

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000359.3(TGM1):​c.614T>A​(p.Leu205Gln) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L205L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.72
• Publications: 1 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: Myriad Women's Health, Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 8 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, lamellar ichthyosis, congenital non-bullous ichthyosiform erythroderma, self-healing collodion baby, bathing suit ichthyosis, acral self-healing collodion baby.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 14-24260593-A-T is Pathogenic according to our data. Variant chr14-24260593-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39526.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.614T>A	p.Leu205Gln	missense	Exon 4 of 15	NP_000350.1	P22735-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.614T>A	p.Leu205Gln	missense	Exon 4 of 15	ENSP00000206765.6	P22735-1
	TGM1	ENST00000879556.1		c.614T>A	p.Leu205Gln	missense	Exon 3 of 14	ENSP00000549615.1
	TGM1	ENST00000544573.5	TSL:2	c.-29+1534T>A		intron	N/A	ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive congenital ichthyosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.7
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
PromoterAI		0.010	Neutral
Varity_R		0.56
gMVP		0.89
Mutation Taster		=73/27	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs878853259;

hg19: chr14-24729799;