rs214814

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1509 hom., cov: 31)

Exomes 𝑓: 0.11 ( 9498 hom. )

Consequence

TGM3
NM_003245.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.243

Publications

22 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
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
uncombable hair syndrome 2
Inheritance: AR Classification: LIMITED Submitted by: G2P

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=0.0022105575).

BP6

Variant 20-2317144-G-A is Benign according to our data. Variant chr20-2317144-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TGM3	NM_003245.4 link	c.746G>A	p.Ser249Asn	missense_variant	Exon 6 of 13	ENST00000381458.6	NP_003236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGM3	ENST00000381458.6 link	c.746G>A	p.Ser249Asn	missense_variant	Exon 6 of 13	1	NM_003245.4	ENSP00000370867.5	Q08188
ENSG00000286022	ENST00000651531.1 link	c.803G>A	p.Ser268Asn	missense_variant	Exon 7 of 14			ENSP00000498584.1	A0A494C0J7
TGM3	ENST00000463090.1 link	n.126G>A		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20168

AN:

152046

Hom.:

1490

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.109

AC:

27313

AN:

251338

AF XY:

0.107

show subpopulations

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 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.:

AF XY:

0.110

AC XY:

79685

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.199

AC:

6649

AN:

33470

American (AMR)

AF:

0.0856

AC:

3827

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3248

AN:

26136

East Asian (EAS)

AF:

0.0732

AC:

2907

AN:

39700

South Asian (SAS)

AF:

0.0679

AC:

5857

AN:

86242

European-Finnish (FIN)

AF:

0.112

AC:

5967

AN:

53420

Middle Eastern (MID)

AF:

0.153

AC:

873

AN:

5692

European-Non Finnish (NFE)

AF:

0.113

AC:

125460

AN:

1111992

Other (OTH)

AF:

0.112

AC:

6783

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

8955

17910

26864

35819

44774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4556

9112

13668

18224

22780

<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:

0.133

AC:

20219

AN:

152164

Hom.:

1509

Cov.:

AF XY:

0.130

AC XY:

9654

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.192

AC:

7962

AN:

41486

American (AMR)

AF:

0.105

AC:

1609

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

441

AN:

3470

East Asian (EAS)

AF:

0.0834

AC:

432

AN:

5178

South Asian (SAS)

AF:

0.0626

AC:

302

AN:

4828

European-Finnish (FIN)

AF:

0.109

AC:

1153

AN:

10590

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7895

AN:

68008

Other (OTH)

AF:

0.143

AC:

303

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

896

1792

2687

3583

4479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.121

Hom.:

3979

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

LINK: link

Submissions by phenotype

TGM3-related disorder

Benign:1

Nov 12, 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

0.064

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.7

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.23

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.021

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.015

PhyloP100

0.24

PrimateAI

Benign

0.41

PROVEAN

Benign

0.35

REVEL

Benign

0.22

Sift

Benign

0.59

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.012

MPC

0.074

ClinPred

0.00071

GERP RS

-0.39

Varity_R

0.13

gMVP

0.095

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over