20-2340459-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003245.4(TGM3):ā€‹c.1960G>Cā€‹(p.Gly654Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,613,766 control chromosomes in the GnomAD database, including 361,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.72 ( 40619 hom., cov: 30)
Exomes š‘“: 0.66 ( 320938 hom. )

Consequence

TGM3
NM_003245.4 missense

Scores

18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.635
Variant links:
Genes affected
TGM3 (HGNC:11779): (transglutaminase 3) Transglutaminases are enzymes that catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. While the primary structure of transglutaminases is not conserved, they all have the same amino acid sequence at their active sites and their activity is calcium-dependent. The protein encoded by this gene consists of two polypeptide chains activated from a single precursor protein by proteolysis. The encoded protein is involved the later stages of cell envelope formation in the epidermis and hair follicle. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.7082315E-7).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGM3NM_003245.4 linkuse as main transcriptc.1960G>C p.Gly654Arg missense_variant 13/13 ENST00000381458.6 NP_003236.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGM3ENST00000381458.6 linkuse as main transcriptc.1960G>C p.Gly654Arg missense_variant 13/131 NM_003245.4 ENSP00000370867.5 Q08188
ENSG00000286022ENST00000651531.1 linkuse as main transcriptc.2017G>C p.Gly673Arg missense_variant 14/14 ENSP00000498584.1 A0A494C0J7

Frequencies

GnomAD3 genomes
AF:
0.722
AC:
109648
AN:
151810
Hom.:
40578
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.877
Gnomad AMI
AF:
0.461
Gnomad AMR
AF:
0.719
Gnomad ASJ
AF:
0.516
Gnomad EAS
AF:
0.855
Gnomad SAS
AF:
0.780
Gnomad FIN
AF:
0.721
Gnomad MID
AF:
0.592
Gnomad NFE
AF:
0.630
Gnomad OTH
AF:
0.704
GnomAD3 exomes
AF:
0.709
AC:
177200
AN:
250082
Hom.:
63955
AF XY:
0.705
AC XY:
95298
AN XY:
135234
show subpopulations
Gnomad AFR exome
AF:
0.885
Gnomad AMR exome
AF:
0.761
Gnomad ASJ exome
AF:
0.516
Gnomad EAS exome
AF:
0.858
Gnomad SAS exome
AF:
0.790
Gnomad FIN exome
AF:
0.723
Gnomad NFE exome
AF:
0.636
Gnomad OTH exome
AF:
0.676
GnomAD4 exome
AF:
0.659
AC:
962706
AN:
1461838
Hom.:
320938
Cov.:
70
AF XY:
0.661
AC XY:
480509
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.889
Gnomad4 AMR exome
AF:
0.757
Gnomad4 ASJ exome
AF:
0.521
Gnomad4 EAS exome
AF:
0.865
Gnomad4 SAS exome
AF:
0.789
Gnomad4 FIN exome
AF:
0.718
Gnomad4 NFE exome
AF:
0.630
Gnomad4 OTH exome
AF:
0.674
GnomAD4 genome
AF:
0.722
AC:
109744
AN:
151928
Hom.:
40619
Cov.:
30
AF XY:
0.728
AC XY:
54076
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.877
Gnomad4 AMR
AF:
0.719
Gnomad4 ASJ
AF:
0.516
Gnomad4 EAS
AF:
0.855
Gnomad4 SAS
AF:
0.780
Gnomad4 FIN
AF:
0.721
Gnomad4 NFE
AF:
0.630
Gnomad4 OTH
AF:
0.705
Alfa
AF:
0.590
Hom.:
3269
Bravo
AF:
0.728
TwinsUK
AF:
0.626
AC:
2320
ALSPAC
AF:
0.632
AC:
2437
ESP6500AA
AF:
0.871
AC:
3838
ESP6500EA
AF:
0.615
AC:
5289
ExAC
AF:
0.712
AC:
86432
Asia WGS
AF:
0.802
AC:
2785
AN:
3478
EpiCase
AF:
0.621
EpiControl
AF:
0.617

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
14
DANN
Benign
0.76
DEOGEN2
Benign
0.042
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.093
N
LIST_S2
Benign
0.13
T
MetaRNN
Benign
5.7e-7
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-2.4
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
4.2
N
REVEL
Benign
0.098
Sift
Benign
1.0
T
Sift4G
Benign
0.99
T
Polyphen
0.0
B
Vest4
0.025
MutPred
0.14
Loss of ubiquitination at K652 (P = 0.0508);
MPC
0.094
ClinPred
0.0071
T
GERP RS
3.4
Varity_R
0.093
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs214830; hg19: chr20-2321105; COSMIC: COSV67350665; API