1-17270928-C-T

Position:

chr1-17270928-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_StrongBP4BS2

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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 55 hom. )

Consequence

PADI3
NM_016233.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11B:1

Conservation

PhyloP100: 7.38

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 Uncertain_significance. Variant got 3 ACMG points.

PP5

Variant 1-17270928-C-T is Pathogenic according to our data. Variant chr1-17270928-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17270928-C-T is described in UniProt as null. Variant chr1-17270928-C-T is described in Lovd as [Pathogenic].

BP4

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

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PADI3	NM_016233.2 linkuse as main transcript	c.881C>T	p.Ala294Val	missense_variant	8/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3 linkuse as main transcript	c.767C>T	p.Ala256Val	missense_variant	8/16		XP_011539873.1
PADI3	XM_017001463.2 linkuse as main transcript	c.344C>T	p.Ala115Val	missense_variant	5/13		XP_016856952.1
PADI3	XM_011541572.3 linkuse as main transcript	c.881C>T	p.Ala294Val	missense_variant	8/12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3 linkuse as main transcript	c.881C>T	p.Ala294Val	missense_variant	8/16	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

GnomAD3 exomes

AF:

0.00677

AC:

1703

AN:

251382

Hom.:

AF XY:

0.00699

AC XY:

950

AN XY:

135866

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 SAS exome

AF:

0.00516

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

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.0162

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00587

Gnomad4 FIN exome

AF:

0.00726

Gnomad4 NFE exome

AF:

0.00839

Gnomad4 OTH exome

AF:

0.00692

GnomAD4 genome

AF:

0.00623

AC:

948

AN:

152268

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

463

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00678

Gnomad4 NFE

AF:

0.00932

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00809

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Benign:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PADI3: PM3:Very Strong, PM2:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	- -

Uncombable hair syndrome 1

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	May 25, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Sep 24, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 14, 2024	- -

PADI3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

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

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

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

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

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