rs142404759

Positions:

• chr14-24255450-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000359.3(TGM1):​c.1559A>G​(p.Glu520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,614,004 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (64 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.59

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060895383).
• BP6: Variant 14-24255450-T-C is Benign according to our data. Variant chr14-24255450-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr14-24255450-T-C is described in UniProt as null. Variant chr14-24255450-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00534 (813/152118) while in subpopulation NFE AF= 0.00918 (624/67996). AF 95% confidence interval is 0.00858. There are 5 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3	c.1559A>G	p.Glu520Gly	missense_variant	11/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11	c.1559A>G	p.Glu520Gly	missense_variant	11/15	1	NM_000359.3	P1
TGM1	ENST00000544573.5	c.233A>G	p.Glu78Gly	missense_variant	5/9	2
TGM1	ENST00000559136.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 813 AN: 152000 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00918

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00571 AC: 1435 AN: 251384 Hom.: 5 AF XY: 0.00564 AC XY: 766 AN XY: 135890

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00826 AC: 12070 AN: 1461886 Hom.: 64 Cov.: 34 AF XY: 0.00809 AC XY: 5886 AN XY: 727244

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00584

Gnomad4 NFE exome AF: 0.00997

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152118 Hom.: 5 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74360

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00623

Gnomad4 NFE AF: 0.00918

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00795 Hom.: 4

Bravo AF: 0.00526

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00567 AC: 688

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TGM1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 31642606, 27025581, 11348475, 21228398) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive congenital ichthyosis 1 Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 21, 2022

- -

TGM1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.72	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.52
Sift	Benign	0.085	T;D
Sift4G	Benign	0.086	T;T
Polyphen		0.96	P;.
Vest4		0.21
MVP		0.93
MPC		0.98
ClinPred		0.036	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.58

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: rs142404759; hg19: chr14-24724656;