chr20-2340459-G-C

Position:

• chr20-2340459-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003245.4(TGM3):​c.1960G>C​(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: 𝑓 0.72 (40619 hom., cov: 30)
  • Exomes 𝑓: 0.66 (320938 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635

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]

ENSG00000286022 (HGNC:):

ACMG classification

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
TGM3	NM_003245.4	c.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
TGM3	ENST00000381458.6	c.1960G>C	p.Gly654Arg	missense_variant	13/13	1	NM_003245.4	ENSP00000370867.5
ENSG00000286022	ENST00000651531.1	c.2017G>C	p.Gly673Arg	missense_variant	14/14			ENSP00000498584.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109648 AN: 151810 Hom.: 40578 Cov.: 30

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

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

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

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

Other links and lift over

dbSNP: rs214830; hg19: chr20-2321105; COSMIC: COSV67350665;