NM_000359.3:c.2225+1457T>C

Variant names:

• chr14-24252695-A-G
• rs2748531
• NM_000359.3:c.2225+1457T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000359.3(TGM1):​c.2225+1457T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 152,200 control chromosomes in the GnomAD database, including 59,488 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (59488 hom., cov: 32)
• Consequence: TGM1 NM_000359.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.460
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.2225+1457T>C		intron	N/A	NP_000350.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.2225+1457T>C		intron	N/A	ENSP00000206765.6
	TGM1	ENST00000544573.5	TSL:2	c.899+1457T>C		intron	N/A	ENSP00000439446.1

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134366 AN: 152080 Hom.: 59425 Cov.: 32

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.915

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.886

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

GnomAD4 genome AF: 0.884 AC: 134488 AN: 152200 Hom.: 59488 Cov.: 32 AF XY: 0.882 AC XY: 65648 AN XY: 74400

African (AFR) AF: 0.913 AC: 37934 AN: 41534

American (AMR) AF: 0.915 AC: 13998 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 3026 AN: 3468

East Asian (EAS) AF: 0.915 AC: 4733 AN: 5172

South Asian (SAS) AF: 0.886 AC: 4279 AN: 4828

European-Finnish (FIN) AF: 0.821 AC: 8684 AN: 10582

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58872 AN: 67994

Other (OTH) AF: 0.887 AC: 1876 AN: 2114

Alfa AF: 0.877 Hom.: 174488

Bravo AF: 0.894

Asia WGS AF: 0.917 AC: 3189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.80
DANN	Benign	0.47
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs2748531; hg19: chr14-24721901;