rs2229464

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000206765.11(TGM1):​c.1819C>T​(p.Arg607Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,614,146 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R607H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 7 hom., cov: 33)
Exomes 𝑓: 0.00044 ( 6 hom. )

Consequence

TGM1
ENST00000206765.11 missense

Scores

4
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.167
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.006229013).
BP6
Variant 14-24255080-G-A is Benign according to our data. Variant chr14-24255080-G-A is described in ClinVar as [Benign]. Clinvar id is 709472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00393 (599/152312) while in subpopulation AFR AF= 0.014 (582/41558). AF 95% confidence interval is 0.0131. There are 7 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGM1NM_000359.3 linkuse as main transcriptc.1819C>T p.Arg607Cys missense_variant 12/15 ENST00000206765.11 NP_000350.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGM1ENST00000206765.11 linkuse as main transcriptc.1819C>T p.Arg607Cys missense_variant 12/151 NM_000359.3 ENSP00000206765 P1P22735-1
TGM1ENST00000544573.5 linkuse as main transcriptc.493C>T p.Arg165Cys missense_variant 6/92 ENSP00000439446 P22735-2
TGM1ENST00000559669.1 linkuse as main transcript upstream_gene_variant 3 ENSP00000453701

Frequencies

GnomAD3 genomes
AF:
0.00392
AC:
597
AN:
152194
Hom.:
7
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0140
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00109
AC:
274
AN:
251364
Hom.:
0
AF XY:
0.000758
AC XY:
103
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.0152
Gnomad AMR exome
AF:
0.000520
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000438
AC:
640
AN:
1461834
Hom.:
6
Cov.:
34
AF XY:
0.000393
AC XY:
286
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0160
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.000580
GnomAD4 genome
AF:
0.00393
AC:
599
AN:
152312
Hom.:
7
Cov.:
33
AF XY:
0.00388
AC XY:
289
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0140
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.000570
Hom.:
0
Bravo
AF:
0.00458
ESP6500AA
AF:
0.0188
AC:
83
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00140
AC:
170
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Benign:3
Benign, no assertion criteria providedclinical testingNatera, Inc.Apr 17, 2020- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 29, 2017This 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024TGM1: BP4, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
TGM1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 27, 2020This variant is classified as 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
0.10
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.21
N
MetaRNN
Benign
0.0062
T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Uncertain
2.2
M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Benign
0.20
Sift
Benign
0.067
T;T
Sift4G
Uncertain
0.053
T;T
Polyphen
0.95
P;.
Vest4
0.28
MVP
0.72
MPC
0.77
ClinPred
0.047
T
GERP RS
-0.027
Varity_R
0.17
gMVP
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2229464; hg19: chr14-24724286; API