rs1555306304

Variant names:

• chr14-24260572-G-A
• rs1555306304
• NM_000359.3:c.635C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000359.3(TGM1):​c.635C>T​(p.Ser212Phe) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S212S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.43
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, G2P
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000359.3
• 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 autosomal recessive congenital ichthyosis 1, acral self-healing collodion baby, bathing suit ichthyosis, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis, self-healing collodion baby.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 14-24260572-G-A is Pathogenic according to our data. Variant chr14-24260572-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552052.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.635C>T	p.Ser212Phe	missense	Exon 4 of 15	NP_000350.1	P22735-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.635C>T	p.Ser212Phe	missense	Exon 4 of 15	ENSP00000206765.6	P22735-1
	TGM1	ENST00000879556.1		c.635C>T	p.Ser212Phe	missense	Exon 3 of 14	ENSP00000549615.1
	TGM1	ENST00000544573.5	TSL:2	c.-29+1555C>T		intron	N/A	ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Autosomal recessive congenital ichthyosis 1 (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.016	D
Sift4G	Benign	0.086	T
Polyphen		0.88	P
Vest4		0.56
MutPred		0.87		Loss of disorder (P = 0.0838)
MVP		0.97
MPC		0.82
ClinPred		0.97	D
GERP RS		6.0
PromoterAI		-0.038	Neutral
Varity_R		0.66
gMVP		0.79
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555306304; hg19: chr14-24729778;