20-2311076-A-C

Variant names:

• chr20-2311076-A-C
• rs6048066
• NM_003245.4:c.487A>C

Variant summary

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

The NM_003245.4(TGM3):​c.487A>C​(p.Ile163Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,614,048 control chromosomes in the GnomAD database, including 5,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (2829 hom., cov: 32)
  • Exomes 𝑓: 0.011 (2495 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.22

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028204918).
• BP6: Variant 20-2311076-A-C is Benign according to our data. Variant chr20-2311076-A-C is described in ClinVar as [Benign]. Clinvar id is 3060634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-2311076-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM3	NM_003245.4	c.487A>C	p.Ile163Leu	missense_variant	Exon 4 of 13	ENST00000381458.6	NP_003236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM3	ENST00000381458.6	c.487A>C	p.Ile163Leu	missense_variant	Exon 4 of 13	1	NM_003245.4	ENSP00000370867.5
ENSG00000286022	ENST00000651531.1	c.544A>C	p.Ile182Leu	missense_variant	Exon 5 of 14			ENSP00000498584.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15925 AN: 152090 Hom.: 2823 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0793

GnomAD3 exomes AF: 0.0272 AC: 6831 AN: 251408 Hom.: 1086 AF XY: 0.0194 AC XY: 2638 AN XY: 135874

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0109 AC: 15931 AN: 1461840 Hom.: 2495 Cov.: 31 AF XY: 0.00943 AC XY: 6858 AN XY: 727218

Gnomad4 AFR exome AF: 0.375

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.105 AC: 15960 AN: 152208 Hom.: 2829 Cov.: 32 AF XY: 0.100 AC XY: 7473 AN XY: 74450

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.0785

Alfa AF: 0.0158 Hom.: 632

Bravo AF: 0.121

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.341 AC: 1503

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0340 AC: 4127

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TGM3-related disorder Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.91	P
Vest4		0.11
MPC		0.085
ClinPred		0.086	T
GERP RS		5.7
Varity_R		0.39
gMVP		0.53

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: rs6048066; hg19: chr20-2291722;