rs214803

chr20-2309687-C-Achr20-2309687-C-Gchr20-2309687-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003245.4(TGM3):c.38C>A(p.Thr13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 1,613,856 control chromosomes in the GnomAD database, including 535,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.73 (42987 hom., cov: 32)
  • Exomes 𝑓: 0.82 (492787 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.43

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.677294E-7).
• BP6: Variant 20-2309687-C-A is Benign according to our data. Variant chr20-2309687-C-A is described in ClinVar as [Benign]. Clinvar id is 3060440.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM3	NM_003245.4	c.38C>A	p.Thr13Lys	missense_variant	2/13	ENST00000381458.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM3	ENST00000381458.6	c.38C>A	p.Thr13Lys	missense_variant	2/13	1	NM_003245.4	P1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111525 AN: 151970 Hom.: 42964 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.756

GnomAD3 exomes AF: 0.819 AC: 205989 AN: 251430 Hom.: 85798 AF XY: 0.823 AC XY: 111783 AN XY: 135890

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.933

Gnomad SAS exome AF: 0.837

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.821

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.818 AC: 1196237 AN: 1461768 Hom.: 492787 Cov.: 67 AF XY: 0.819 AC XY: 595705 AN XY: 727182

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.887

Gnomad4 ASJ exome AF: 0.780

Gnomad4 EAS exome AF: 0.946

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.859

Gnomad4 NFE exome AF: 0.821

Gnomad4 OTH exome AF: 0.803

GnomAD4 genome AF: 0.734 AC: 111603 AN: 152088 Hom.: 42987 Cov.: 32 AF XY: 0.740 AC XY: 55046 AN XY: 74352

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.839

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.934

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.859

Gnomad4 NFE AF: 0.823

Gnomad4 OTH AF: 0.758

Alfa AF: 0.803 Hom.: 92748

Bravo AF: 0.720

TwinsUK AF: 0.821 AC: 3044

ALSPAC AF: 0.822 AC: 3169

ESP6500AA AF: 0.485 AC: 2137

ESP6500EA AF: 0.821 AC: 7058

ExAC AF: 0.810 AC: 98372

Asia WGS AF: 0.877 AC: 3052 AN: 3478

EpiCase AF: 0.813

EpiControl AF: 0.806

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TGM3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2019

This 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	0.090
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.0080
Dann	Benign	0.44
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.17
Sift	Benign	0.69	T
Sift4G	Benign	0.64	T
Polyphen		0.73	P
Vest4		0.037
MPC		0.096
ClinPred		0.0052	T
GERP RS		-1.1
Varity_R		0.17
gMVP		0.42

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: rs214803; hg19: chr20-2290333; COSMIC: COSV67350838; COSMIC: COSV67350838;