rs139426141

Positions:

• chr1-17270903-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 8.72

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 submissions are: {Uncertain_significance=1, Pathogenic=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI3	NM_016233.2	c.856A>G	p.Thr286Ala	missense_variant	8/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3	c.742A>G	p.Thr248Ala	missense_variant	8/16		XP_011539873.1
PADI3	XM_017001463.2	c.319A>G	p.Thr107Ala	missense_variant	5/13		XP_016856952.1
PADI3	XM_011541572.3	c.856A>G	p.Thr286Ala	missense_variant	8/12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3	c.856A>G	p.Thr286Ala	missense_variant	8/16	1	NM_016233.2	ENSP00000364609.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1581 AN: 151880 Hom.: 32 Cov.: 32

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

GnomAD3 exomes AF: 0.00271 AC: 682 AN: 251394 Hom.: 15 AF XY: 0.00208 AC XY: 282 AN XY: 135866

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 SAS exome AF: 0.000163

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.: 20 Cov.: 33 AF XY: 0.000963 AC XY: 700 AN XY: 727228

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.0104 AC: 1582 AN: 152000 Hom.: 32 Cov.: 32 AF XY: 0.0100 AC XY: 744 AN XY: 74286

Gnomad4 AFR AF: 0.0358

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00483 Hom.: 7

Bravo AF: 0.0119

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00363 AC: 441

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Central centrifugal cicatricial alopecia Pathogenic:1 Benign:1

Benign, no assertion criteria provided	literature only	OMIM	Jan 07, 2025	- -
Pathogenic, criteria provided, single submitter	research	Molecular Dermatology Lab, Tel Aviv Sourasky Medical Center	Jul 01, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.23
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		0.95	P
Vest4		0.87
MVP		0.44
MPC		0.13
ClinPred		0.089	T
GERP RS		5.5
Varity_R		0.37
gMVP		0.53

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

Other links and lift over

dbSNP: rs139426141; hg19: chr1-17597398;