rs398122902

chr14-24254969-TACAGGCC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_000359.3(TGM1):c.1923_1927+2del variant causes a splice donor, coding sequence change. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM1 NM_000359.3 splice_donor, coding_sequence
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.057253465 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• 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/exons	MANE	UniProt
TGM1	NM_000359.3	c.1923_1927+2del		splice_donor_variant, coding_sequence_variant	12/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11	c.1923_1927+2del		splice_donor_variant, coding_sequence_variant	12/15	1	NM_000359.3	P1
TGM1	ENST00000544573.5	c.597_601+2del		splice_donor_variant, coding_sequence_variant	6/9	2
TGM1	ENST00000559669.1	c.81_85+2del		splice_donor_variant, coding_sequence_variant	1/3	3

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 19, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2009	- -

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;