NM_000359.3:c.1923_1927+2delGGCCTGT

Variant names:

• chr14-24254969-TACAGGCC-T
• rs398122902
• NM_000359.3:c.1923_1927+2delGGCCTGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000359.3(TGM1):​c.1923_1927+2delGGCCTGT​(p.Ala642fs) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G641G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM1 NM_000359.3 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.56

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-24254969-TACAGGCC-T is Pathogenic according to our data. Variant chr14-24254969-TACAGGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 39534.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.1923_1927+2delGGCCTGT	p.Ala642fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 12 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.1923_1927+2delGGCCTGT	p.Ala642fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 12 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5	c.597_601+2delGGCCTGT	p.Ala200fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 9	2		ENSP00000439446.1
TGM1	ENST00000559669.1	c.81_85+2delGGCCTGT	p.Ala28fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 3	3		ENSP00000453701.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:2

Jan 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122902; hg19: chr14-24724175;