chr1-17259639-A-G

Position:

• chr1-17259639-A-G

Variant summary

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

The NM_016233.2(PADI3):​c.154A>G​(p.Ile52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 1,613,328 control chromosomes in the GnomAD database, including 8,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.093 (698 hom., cov: 33)
  • Exomes 𝑓: 0.098 (7870 hom.)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0130

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=0.002042234).
• BP6: Variant 1-17259639-A-G is Benign according to our data. Variant chr1-17259639-A-G is described in ClinVar as [Benign]. Clinvar id is 3059385.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI3	NM_016233.2	c.154A>G	p.Ile52Val	missense_variant	2/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3	c.40A>G	p.Ile14Val	missense_variant	2/16		XP_011539873.1
PADI3	XM_011541572.3	c.154A>G	p.Ile52Val	missense_variant	2/12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3	c.154A>G	p.Ile52Val	missense_variant	2/16	1	NM_016233.2	ENSP00000364609	P1

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14109 AN: 152144 Hom.: 696 Cov.: 33

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0876

Gnomad OTH AF: 0.0928

GnomAD3 exomes AF: 0.109 AC: 27311 AN: 250788 Hom.: 1783 AF XY: 0.113 AC XY: 15300 AN XY: 135510

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0982 AC: 143513 AN: 1461066 Hom.: 7870 Cov.: 31 AF XY: 0.101 AC XY: 73618 AN XY: 726772

Gnomad4 AFR exome AF: 0.0799

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.0605

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.0902

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.0927 AC: 14117 AN: 152262 Hom.: 698 Cov.: 33 AF XY: 0.0941 AC XY: 7008 AN XY: 74452

Gnomad4 AFR AF: 0.0821

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0573

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.0639

Gnomad4 NFE AF: 0.0876

Gnomad4 OTH AF: 0.0952

Alfa AF: 0.0915 Hom.: 1817

Bravo AF: 0.0947

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0981 AC: 378

ESP6500AA AF: 0.0833 AC: 367

ESP6500EA AF: 0.0919 AC: 790

ExAC AF: 0.109 AC: 13274

Asia WGS AF: 0.173 AC: 602 AN: 3476

EpiCase AF: 0.0898

EpiControl AF: 0.0932

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	0.070
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0080
DANN	Benign	0.43
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.084
ClinPred		0.0012	T
GERP RS		0.16
Varity_R		0.13
gMVP		0.096

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: rs3750300; hg19: chr1-17586134; COSMIC: COSV64934254;