14-24259099-C-T

Position:

• chr14-24259099-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000359.3(TGM1):​c.1135G>A​(p.Val379Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V379L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259099-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3	c.1135G>A	p.Val379Ile	missense_variant	7/15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.1135G>A	p.Val379Ile	missense_variant	7/15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000559136.1	c.208G>A	p.Val70Ile	missense_variant	3/7	5		ENSP00000453337.1
TGM1	ENST00000544573.5	c.-28-711G>A		intron_variant		2		ENSP00000439446.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.98	N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;.
Polyphen		0.83	P;.
Vest4		0.45
MutPred		0.83		Loss of catalytic residue at V379 (P = 0.0978);.;
MVP		0.90
MPC		0.80
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.61
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918720; hg19: chr14-24728305;