14-24259160-G-C

Variant names:

• chr14-24259160-G-C
• rs779287673
• NM_000359.3:c.1074C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000359.3(TGM1):​c.1074C>G​(p.Ser358Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S358N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.0990
• Publications: 5 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000359.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259161-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3008283.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.95
• PP5: Variant 14-24259160-G-C is Pathogenic according to our data. Variant chr14-24259160-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 553856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1074C>G	p.Ser358Arg	missense	Exon 7 of 15	NP_000350.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.1074C>G	p.Ser358Arg	missense	Exon 7 of 15	ENSP00000206765.6
	TGM1	ENST00000559136.1	TSL:5	c.147C>G	p.Ser49Arg	missense	Exon 3 of 7	ENSP00000453337.1
	TGM1	ENST00000544573.5	TSL:2	c.-28-772C>G		intron	N/A	ENSP00000439446.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251142 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461820 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111986

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:4

Feb 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 06, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 15, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lamellar ichthyosis Pathogenic:1

Oct 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGM1 c.1074C>G (p.Ser358Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251142 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (4.4e-05 vs 0.0021), allowing no conclusion about variant significance. c.1074C>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Lamellar Ichthyosis (e.g. Pigg_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27025581). ClinVar contains an entry for this variant (Variation ID: 553856). Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:1

Mar 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 358 of the TGM1 protein (p.Ser358Arg). This variant is present in population databases (rs779287673, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 9261103, 27025581, 28403434). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGM1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.59	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		-0.099
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.85		Gain of methylation at S358 (P = 0.0415)
MVP		0.99
MPC		0.98
ClinPred		0.99	D
GERP RS		0.28
Varity_R		0.96
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs779287673; hg19: chr14-24728366;