rs144080386

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_016233.2(PADI3):c.881C>T(p.Ala294Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,098 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 55 hom. )

Consequence

PADI3
NM_016233.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12B:1

Conservation

PhyloP100: 7.38

Publications

17 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
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: Likely_benign. The variant received -5 ACMG points.

PP5

Variant 1-17270928-C-T is Pathogenic according to our data. Variant chr1-17270928-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374867.

BP4

Computational evidence support a benign effect (MetaRNN=0.02340281). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00623 (948/152268) while in subpopulation NFE AF = 0.00932 (634/68008). AF 95% confidence interval is 0.00872. There are 7 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 7 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PADI3	NM_016233.2 link	c.881C>T	p.Ala294Val	missense_variant	Exon 8 of 16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3 link	c.767C>T	p.Ala256Val	missense_variant	Exon 8 of 16		XP_011539873.1
PADI3	XM_017001463.2 link	c.344C>T	p.Ala115Val	missense_variant	Exon 5 of 13		XP_016856952.1
PADI3	XM_011541572.3 link	c.881C>T	p.Ala294Val	missense_variant	Exon 8 of 12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3 link	c.881C>T	p.Ala294Val	missense_variant	Exon 8 of 16	1	NM_016233.2	ENSP00000364609.3		Q9ULW8

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

948

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00678

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00932

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00677

AC:

1703

AN:

251382

AF XY:

0.00699

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00698

Gnomad NFE exome

AF:

0.00922

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00770

AC:

11256

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

5607

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33480

American (AMR)

AF:

0.00309

AC:

138

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

423

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00587

AC:

506

AN:

86258

European-Finnish (FIN)

AF:

0.00726

AC:

388

AN:

53410

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00839

AC:

9328

AN:

1111962

Other (OTH)

AF:

0.00692

AC:

418

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

565

1130

1696

2261

2826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00623

AC:

948

AN:

152268

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

463

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41562

American (AMR)

AF:

0.00549

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00456

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00678

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00932

AC:

634

AN:

68008

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00781

Hom.:

Bravo

AF:

0.00549

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00666

AC:

809

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Uncombable hair syndrome 1

Pathogenic:6

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_016233.2:c.881C>T in the PADI3 gene has an allele frequency of 0.017 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that c.881C>T has affected transglutaminase activity of TGM3 produced in HEK293T cells (PMID: 27866708). It was detected in multiple individuals with autosomal recessive Uncombable hair syndrome, homozygous c.881C> T(p.Ala294Val), compound heterozygous with c.335T>A (p.Leu112His) ,c.1732A>T (p.Lys578*)(PMID: 27866708). The patient's phenotype is highly specific for PADI3 gene(PMID: 27866708). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. -

May 25, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 24, 2024

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PADI3 c.881C>T (p.Ala294Val) variant (rs144080386) is cited by previous literature (Basmanav et al. 2016. PubMed ID 27866708). This variant is reported as pathogenic by laboratories in ClinVar (Variation ID: 374867). GnomAD 4.1.0 frequency is 0.007561 with 62 homozygotes. It is an OMIM variant: https://omim.org/entry/606755#0001. Prediction of the impact of the variant on the resulting protein and immunofluorescence studies were performed by Basmanav et al. 2016 with results coherent with modified function. -

Sep 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:5Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PADI3: PM3:Very Strong, PM2:Supporting -

Jun 19, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect; specifically, the A294V variant is associated with decreased enzyme activity and abnormal enzyme aggregation (Basmanav et al., 2016).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29756256, 22381266, 27866708, 31952341, 34426522, 35279260, 24629392) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PADI3-related disorder

Pathogenic:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PADI3 c.881C>T variant is predicted to result in the amino acid substitution p.Ala294Val. This variant has been reported in both the homozygous and heterozygous states as causative for uncombable hair syndrome in several patients (Basmanav et al. 2016. PubMed ID: 27866708; Drivenes et al. 2022. PubMed ID: 35279260). This variant was observed in a public database with allele frequency up to ~0.90% in European populations and 1.75% in Ashkenazi Jewish populations, respectively; 15 homozygotes of this variant were also reported out of 282,758 alleles. Although this variant is common in the general population, it is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.1

PhyloP100

7.4

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MVP

0.51

MPC

0.51

ClinPred

0.025

GERP RS

5.5

Varity_R

0.76

gMVP

0.77

Mutation Taster

=67/33

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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