chr14-24249377-G-A

Variant names:

• chr14-24249377-G-A
• NM_000359.3:c.2390C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000359.3(TGM1):​c.2390C>T​(p.Ser797Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.27

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

Our verdict: Uncertain_significance. The variant received 1 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 bathing suit ichthyosis, self-healing collodion baby, lamellar ichthyosis, acral self-healing collodion baby, autosomal recessive congenital ichthyosis 1, congenital non-bullous ichthyosiform erythroderma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16419742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.2390C>T	p.Ser797Leu	missense_variant	Exon 15 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.2390C>T	p.Ser797Leu	missense_variant	Exon 15 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5	c.1064C>T	p.Ser355Leu	missense_variant	Exon 9 of 9	2		ENSP00000439446.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Uncertain:1

Apr 07, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		3.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.28	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;.
Vest4		0.45
MutPred		0.32		Loss of glycosylation at S797 (P = 0.0127);.;
MVP		0.84
MPC		0.23
ClinPred		0.61	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.29
Mutation Taster		=97/3	polymorphism

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

Publications

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Other links and lift over

hg19: chr14-24718583;