14-24260481-C-T

Position:

• chr14-24260481-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000359.3(TGM1):​c.726G>A​(p.Glu242Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,194 control chromosomes in the GnomAD database, including 1,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (292 hom., cov: 33)
  • Exomes 𝑓: 0.025 (811 hom.)
• Consequence: TGM1 NM_000359.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.133

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 14-24260481-C-T is Benign according to our data. Variant chr14-24260481-C-T is described in ClinVar as [Benign]. Clinvar id is 255942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24260481-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.133 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3	c.726G>A	p.Glu242Glu	synonymous_variant	4/15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.726G>A	p.Glu242Glu	synonymous_variant	4/15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5	c.-29+1646G>A		intron_variant		2		ENSP00000439446.1

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7375 AN: 152188 Hom.: 291 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.0662

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0368 AC: 9257 AN: 251412 Hom.: 269 AF XY: 0.0377 AC XY: 5130 AN XY: 135902

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0445

Gnomad EAS exome AF: 0.0795

Gnomad SAS exome AF: 0.0657

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0367

GnomAD4 exome AF: 0.0254 AC: 37142 AN: 1461888 Hom.: 811 Cov.: 33 AF XY: 0.0265 AC XY: 19292 AN XY: 727246

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0448

Gnomad4 EAS exome AF: 0.0619

Gnomad4 SAS exome AF: 0.0635

Gnomad4 FIN exome AF: 0.0323

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0485 AC: 7384 AN: 152306 Hom.: 292 Cov.: 33 AF XY: 0.0499 AC XY: 3720 AN XY: 74478

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.0664

Gnomad4 SAS AF: 0.0605

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0361 Hom.: 87

Bravo AF: 0.0502

Asia WGS AF: 0.0500 AC: 172 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0207

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.5
DANN	Benign	0.87

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

LitVar

Other links and lift over

dbSNP: rs35755034; hg19: chr14-24729687;