rs142129409

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 8P and 3B. PP5_Very_StrongBP4BS1_SupportingBS2_Supporting

The NM_016233.2(PADI3):c.335T>A(p.Leu112His) variant causes a missense change. The variant allele was found at a frequency of 0.00699 in 1,608,134 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0049 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 38 hom. )

Consequence

PADI3
NM_016233.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.42

Publications

23 publications found

Variant links:

Genes affected

PADI3 (HGNC:18337): (peptidyl arginine deiminase 3) This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type III enzyme modulates hair structural proteins, such as filaggrin in the hair follicle and trichohyalin in the inner root sheath, during hair follicle formation. Together with the type I enzyme, this enzyme may also play a role in terminal differentiation of the epidermis. This gene exists in a cluster with four other paralogous genes. [provided by RefSeq, Jul 2008]

PADI3 Gene-Disease associations (from GenCC):

uncombable hair syndrome 1
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
uncombable hair syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PADI3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP5

Variant 1-17262194-T-A is Pathogenic according to our data. Variant chr1-17262194-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.03680539). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00721 (10500/1455906) while in subpopulation NFE AF = 0.00846 (9391/1110106). AF 95% confidence interval is 0.00832. There are 38 homozygotes in GnomAdExome4. There are 4993 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016233.2. 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
	PADI3	NM_016233.2	MANE Select	c.335T>A	p.Leu112His	missense	Exon 3 of 16	NP_057317.2	Q9ULW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI3	ENST00000375460.3	TSL:1 MANE Select	c.335T>A	p.Leu112His	missense	Exon 3 of 16	ENSP00000364609.3	Q9ULW8

Frequencies

GnomAD3 genomes

AF:

0.00489

AC:

744

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00753

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00455

AC:

1108

AN:

243658

AF XY:

0.00439

show subpopulations

Gnomad AFR exome

AF:

0.000815

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.00599

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00274

Gnomad NFE exome

AF:

0.00707

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00721

AC:

10500

AN:

1455906

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

4993

AN XY:

724364

show subpopulations

African (AFR)

AF:

0.000998

AC:

AN:

33066

American (AMR)

AF:

0.00414

AC:

178

AN:

42994

Ashkenazi Jewish (ASJ)

AF:

0.00700

AC:

182

AN:

26010

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39434

South Asian (SAS)

AF:

0.00106

AC:

AN:

85020

European-Finnish (FIN)

AF:

0.00341

AC:

182

AN:

53382

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00846

AC:

9391

AN:

1110106

Other (OTH)

AF:

0.00679

AC:

408

AN:

60132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

481

962

1443

1924

2405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.00489

AC:

745

AN:

152228

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41538

American (AMR)

AF:

0.00733

AC:

112

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00753

AC:

512

AN:

68016

Other (OTH)

AF:

0.00569

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00741

Hom.:

Bravo

AF:

0.00540

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00378

AC:

459

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00835

EpiControl

AF:

0.00630

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Uncombable hair syndrome 1 (8)

not provided (6)

PADI3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.041

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.5

PhyloP100

4.4

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MVP

0.50

MPC

0.58

ClinPred

0.034

GERP RS

5.1

Varity_R

0.97

gMVP

0.66

Mutation Taster

=31/69

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over