1-17262194-T-A

Position:

chr1-17262194-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

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:13

Conservation

PhyloP100: 4.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 1-17262194-T-A is Pathogenic according to our data. Variant chr1-17262194-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17262194-T-A is described in UniProt as null. Variant chr1-17262194-T-A is described in Lovd as [Pathogenic]. Variant chr1-17262194-T-A is described in Lovd as [Likely_pathogenic].

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PADI3	NM_016233.2 linkuse as main transcript	c.335T>A	p.Leu112His	missense_variant	3/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3 linkuse as main transcript	c.221T>A	p.Leu74His	missense_variant	3/16		XP_011539873.1
PADI3	XM_011541572.3 linkuse as main transcript	c.335T>A	p.Leu112His	missense_variant	3/12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3 linkuse as main transcript	c.335T>A	p.Leu112His	missense_variant	3/16	1	NM_016233.2	ENSP00000364609	P1

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

GnomAD3 exomes

AF:

0.00455

AC:

1108

AN:

243658

Hom.:

AF XY:

0.00439

AC XY:

580

AN XY:

132024

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 SAS exome

AF:

0.000933

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

Gnomad4 AFR exome

AF:

0.000998

Gnomad4 AMR exome

AF:

0.00414

Gnomad4 ASJ exome

AF:

0.00700

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.00106

Gnomad4 FIN exome

AF:

0.00341

Gnomad4 NFE exome

AF:

0.00846

Gnomad4 OTH exome

AF:

0.00679

GnomAD4 genome

AF:

0.00489

AC:

745

AN:

152228

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00733

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00753

Gnomad4 OTH

AF:

0.00569

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Uncombable hair syndrome 1

Pathogenic:6

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_016233.2:c.335T>A in the PADI3 gene has an allele frequency of 0.007 in European(non-Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.335T>A 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.335T>A, compound heterozygous with c.1813C>A, and c.881C>T, respectively (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, M-CAP, MutationAssessor. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 25, 2023	PS3, PM3_Strong, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 31, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PADI3: PM3:Very Strong, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2024	Published functional studies demonstrate a damaging effect; specifically, the L112H variant is associated with absent enzyme activity and abnormal enzyme aggregation (PMID: 27866708); 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: 31952341, 27866708, 34426522, 34297361, 36044230, 36541401, 36920900, 35751533) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

PADI3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

The PADI3 c.335T>A variant is predicted to result in the amino acid substitution p.Leu112His. This variant has been reported in the homozygous and compound heterozygous states with another variant [c.881C>T (p.Ala294Val)] to be causative for autosomal recessive uncombable hair syndrome in several unrelated patients (Basmanav et al. 2016. PubMed ID: 27866708; OMIM #191480). This variant is reported in 0.70% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

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

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over