rs34097903

chr1-17280779-G-A

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.1744G>A(p.Ala582Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,614,054 control chromosomes in the GnomAD database, including 26 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 0.0066 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.74

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 1-17280779-G-A is Pathogenic according to our data. Variant chr1-17280779-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599195.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013067484).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00657 (1000/152272) while in subpopulation AFR AF= 0.0233 (968/41548). AF 95% confidence interval is 0.0221. There are 16 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI3	NM_016233.2	c.1744G>A	p.Ala582Thr	missense_variant	15/16	ENST00000375460.3
PADI3	XM_011541571.3	c.1630G>A	p.Ala544Thr	missense_variant	15/16
PADI3	XM_017001463.2	c.1207G>A	p.Ala403Thr	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI3	ENST00000375460.3	c.1744G>A	p.Ala582Thr	missense_variant	15/16	1	NM_016233.2	P1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 991 AN: 152154 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00157 AC: 394 AN: 251392 Hom.: 5 AF XY: 0.00112 AC XY: 152 AN XY: 135854

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000614 AC: 898 AN: 1461782 Hom.: 10 Cov.: 32 AF XY: 0.000512 AC XY: 372 AN XY: 727184

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00657 AC: 1000 AN: 152272 Hom.: 16 Cov.: 33 AF XY: 0.00633 AC XY: 471 AN XY: 74462

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000903 Hom.: 1

Bravo AF: 0.00674

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Central centrifugal cicatricial alopecia Pathogenic:1

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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.15
Sift	Benign	0.067	T
Sift4G	Benign	0.18	T
Polyphen		0.96	D
Vest4		0.67
MVP		0.54
MPC		0.38
ClinPred		0.065	T
GERP RS		4.6
Varity_R		0.48
gMVP		0.79

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: rs34097903; hg19: chr1-17607274;