1-17270903-A-G

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.856A>G(p.Thr286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,840 control chromosomes in the GnomAD database, including 52 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 0.010 ( 32 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 20 hom. )

Consequence

PADI3
NM_016233.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 8.72

Publications

7 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 1-17270903-A-G is Pathogenic according to our data. Variant chr1-17270903-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599194.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.018690884). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1582/152000) while in subpopulation AFR AF = 0.0358 (1485/41464). AF 95% confidence interval is 0.0343. There are 32 homozygotes in GnomAd4. There are 744 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 32 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PADI3	NM_016233.2 link	c.856A>G	p.Thr286Ala	missense_variant	Exon 8 of 16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3 link	c.742A>G	p.Thr248Ala	missense_variant	Exon 8 of 16		XP_011539873.1
PADI3	XM_017001463.2 link	c.319A>G	p.Thr107Ala	missense_variant	Exon 5 of 13		XP_016856952.1
PADI3	XM_011541572.3 link	c.856A>G	p.Thr286Ala	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.856A>G	p.Thr286Ala	missense_variant	Exon 8 of 16	1	NM_016233.2	ENSP00000364609.3		Q9ULW8

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1581

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00271

AC:

682

AN:

251394

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00110

AC:

1604

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000963

AC XY:

700

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0365

AC:

1222

AN:

33478

American (AMR)

AF:

0.00210

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000899

AC:

100

AN:

1111978

Other (OTH)

AF:

0.00270

AC:

163

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0104

AC:

1582

AN:

152000

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

744

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0358

AC:

1485

AN:

41464

American (AMR)

AF:

0.00491

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67930

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

150

225

300

375

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:

0.00498

Hom.:

Bravo

AF:

0.0119

ESP6500AA

AF:

0.0390

AC:

172

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00363

AC:

441

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Central centrifugal cicatricial alopecia

Pathogenic:1Benign:1

Jan 07, 2025

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 01, 2018

Molecular Dermatology Lab, Tel Aviv Sourasky Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Uncombable hair syndrome 1

Uncertain:1

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

8.7

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.23

Sift

Benign

0.034

Sift4G

Benign

0.19

Polyphen

0.95

Vest4

0.87

MVP

0.44

MPC

0.13

ClinPred

0.089

GERP RS

5.5

Varity_R

0.37

gMVP

0.53

Mutation Taster

=45/55

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over