chr1-17266821-G-A

Position:

• chr1-17266821-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000375460.3(PADI3):​c.511G>A​(p.Val171Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 1,613,246 control chromosomes in the GnomAD database, including 7,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.076 (533 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6675 hom.)
• Consequence: PADI3 ENST00000375460.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019271374).
• BP6: Variant 1-17266821-G-A is Benign according to our data. Variant chr1-17266821-G-A is described in ClinVar as [Benign]. Clinvar id is 3060283.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI3	NM_016233.2	c.511G>A	p.Val171Met	missense_variant	5/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3	c.397G>A	p.Val133Met	missense_variant	5/16		XP_011539873.1
PADI3	XM_011541572.3	c.511G>A	p.Val171Met	missense_variant	5/12		XP_011539874.1
PADI3	XM_017001463.2	c.-27G>A		5_prime_UTR_variant	2/13		XP_016856952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3	c.511G>A	p.Val171Met	missense_variant	5/16	1	NM_016233.2	ENSP00000364609	P1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11555 AN: 152136 Hom.: 533 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.0772

GnomAD3 exomes AF: 0.103 AC: 25982 AN: 251216 Hom.: 1714 AF XY: 0.109 AC XY: 14735 AN XY: 135784

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.0949

GnomAD4 exome AF: 0.0878 AC: 128257 AN: 1460992 Hom.: 6675 Cov.: 31 AF XY: 0.0913 AC XY: 66341 AN XY: 726884

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.0549

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.0901

GnomAD4 genome AF: 0.0759 AC: 11558 AN: 152254 Hom.: 533 Cov.: 32 AF XY: 0.0810 AC XY: 6028 AN XY: 74452

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0752

Gnomad4 OTH AF: 0.0787

Alfa AF: 0.0752 Hom.: 1047

Bravo AF: 0.0721

TwinsUK AF: 0.0809 AC: 300

ALSPAC AF: 0.0843 AC: 325

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.0800 AC: 688

ExAC AF: 0.101 AC: 12250

Asia WGS AF: 0.171 AC: 593 AN: 3478

EpiCase AF: 0.0782

EpiControl AF: 0.0789

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PADI3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.33	N
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.48	P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Benign	0.050	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.064
MPC		0.51
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.064
gMVP		0.63

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: rs2272629; hg19: chr1-17593316; COSMIC: COSV64935095;