chr14-24261740-G-A

Variant names:

• chr14-24261740-G-A
• rs187901859
• NM_000359.3:c.463C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BS1_Supporting BS2

The NM_000359.3(TGM1):​c.463C>T​(p.Arg155Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,122 control chromosomes in the GnomAD database, including 4 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 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.69

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_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.1773006).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000204 (31/152238) while in subpopulation EAS AF= 0.00599 (31/5176). AF 95% confidence interval is 0.00434. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.463C>T	p.Arg155Trp	missense_variant	Exon 3 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.463C>T	p.Arg155Trp	missense_variant	Exon 3 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5	c.-29+387C>T		intron_variant	Intron 2 of 8	2		ENSP00000439446.1
TGM1	ENST00000558074.1	c.*58C>T		downstream_gene_variant		5		ENSP00000453840.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000509 AC: 128 AN: 251424 Hom.: 2 AF XY: 0.000442 AC XY: 60 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00642

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000252 AC: 369 AN: 1461884 Hom.: 4 Cov.: 32 AF XY: 0.000270 AC XY: 196 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00851

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00599

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000492 Hom.: 1

Bravo AF: 0.000268

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Uncertain:4

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Nov 13, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000359.2(TGM1):c.463C>T(R155W) is a missense variant classified as a variant of uncertain significance in the context of TGM1-related autosomal recessive congenital ichthyosis. R155W has been observed in cases with relevant disease (PMID: 19262603, 25154629, 20021785). Functional assessments of this variant are not available in the literature. R155W has been observed in population frequency databases (gnomAD: EAS 0.65%). In summary, there is insufficient evidence to classify NM_000359.2(TGM1):c.463C>T(R155W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

TGM1-related disorder Benign:1

Jul 09, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

not provided Benign:1

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.98
MPC		0.94
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.86
gMVP		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: rs187901859; hg19: chr14-24730946;