20-2311076-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I163T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 2829 hom., cov: 32)

Exomes 𝑓: 0.011 ( 2495 hom. )

Consequence

TGM3
NM_003245.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.22

Publications

12 publications found

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]

TGM3 Gene-Disease associations (from GenCC):

uncombable hair syndrome 2
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, G2P
uncombable hair syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TGM3 links:

ENSG00000286022 (HGNC:):

ENSG00000286022 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 3060634.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM3	NM_003245.4	MANE Select	c.487A>C	p.Ile163Leu	missense	Exon 4 of 13	NP_003236.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM3	ENST00000381458.6	TSL:1 MANE Select	c.487A>C	p.Ile163Leu	missense	Exon 4 of 13	ENSP00000370867.5	Q08188
	ENSG00000286022	ENST00000651531.1		c.544A>C	p.Ile182Leu	missense	Exon 5 of 14	ENSP00000498584.1	A0A494C0J7

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15925

AN:

152090

Hom.:

2823

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0272

AC:

6831

AN:

251408

AF XY:

0.0194

show subpopulations

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 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.:

AF XY:

0.00943

AC XY:

6858

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.375

AC:

12540

AN:

33472

American (AMR)

AF:

0.0210

AC:

938

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000974

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000678

AC:

754

AN:

1111990

Other (OTH)

AF:

0.0255

AC:

1538

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

582

1164

1747

2329

2911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.105

AC:

15960

AN:

152208

Hom.:

2829

Cov.:

AF XY:

0.100

AC XY:

7473

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.362

AC:

15000

AN:

41462

American (AMR)

AF:

0.0457

AC:

699

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68032

Other (OTH)

AF:

0.0785

AC:

166

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

515

1030

1544

2059

2574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0347

Hom.:

2244

Bravo

AF:

0.121

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.341

AC:

1503

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.0340

AC:

4127

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TGM3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.5

PhyloP100

3.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.020

Polyphen

0.91

Vest4

0.11

MPC

0.085

ClinPred

0.086

GERP RS

5.7

Varity_R

0.39

gMVP

0.53

Mutation Taster

=49/51

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over