rs214814

Positions:

• chr20-2317144-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003245.4(TGM3):​c.746G>A​(p.Ser249Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,926 control chromosomes in the GnomAD database, including 11,007 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1509 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9498 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.243

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022105575).
• BP6: Variant 20-2317144-G-A is Benign according to our data. Variant chr20-2317144-G-A is described in ClinVar as [Benign]. Clinvar id is 3061032.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM3	NM_003245.4	c.746G>A	p.Ser249Asn	missense_variant	6/13	ENST00000381458.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM3	ENST00000381458.6	c.746G>A	p.Ser249Asn	missense_variant	6/13	1	NM_003245.4	P1
TGM3	ENST00000463090.1	n.126G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20168 AN: 152046 Hom.: 1490 Cov.: 31

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0840

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.109 AC: 27313 AN: 251338 Hom.: 1667 AF XY: 0.107 AC XY: 14570 AN XY: 135838

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0855

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0792

Gnomad SAS exome AF: 0.0683

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.111 AC: 161571 AN: 1461762 Hom.: 9498 Cov.: 33 AF XY: 0.110 AC XY: 79685 AN XY: 727174

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.0856

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0732

Gnomad4 SAS exome AF: 0.0679

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.133 AC: 20219 AN: 152164 Hom.: 1509 Cov.: 31 AF XY: 0.130 AC XY: 9654 AN XY: 74400

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.0834

Gnomad4 SAS AF: 0.0626

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.143

Alfa AF: 0.118 Hom.: 1907

Bravo AF: 0.136

TwinsUK AF: 0.104 AC: 386

ALSPAC AF: 0.104 AC: 399

ESP6500AA AF: 0.200 AC: 881

ESP6500EA AF: 0.115 AC: 992

ExAC AF: 0.112 AC: 13611

Asia WGS AF: 0.133 AC: 465 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TGM3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 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	0.064
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.51
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.021	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.015	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.22
Sift	Benign	0.59	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.074
ClinPred		0.00071	T
GERP RS		-0.39
Varity_R		0.13
gMVP		0.095

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: rs214814; hg19: chr20-2297790; COSMIC: COSV67352542;