rs874881

chr1-17334004-G-Cchr1-17334004-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012387.3(PADI4):c.335G>C(p.Gly112Ala) variant causes a missense change. The variant allele was found at a frequency of 0.554 in 1,602,266 control chromosomes in the GnomAD database, including 247,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (21992 hom., cov: 31)
  • Exomes 𝑓: 0.56 (225758 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.69

Genes affected

PADI4 (HGNC:18368): (peptidyl arginine deiminase 4) This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine residues to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.706947E-5).
• BP6: Variant 1-17334004-G-C is Benign according to our data. Variant chr1-17334004-G-C is described in ClinVar as [Benign]. Clinvar id is 972895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI4	NM_012387.3	c.335G>C	p.Gly112Ala	missense_variant	3/16	ENST00000375448.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI4	ENST00000375448.4	c.335G>C	p.Gly112Ala	missense_variant	3/16	1	NM_012387.3	P1
PADI4	ENST00000375453.5	c.335G>C	p.Gly112Ala	missense_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81347 AN: 151744 Hom.: 22001 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.545 AC: 136995 AN: 251246 Hom.: 37763 AF XY: 0.549 AC XY: 74563 AN XY: 135810

Gnomad AFR exome AF: 0.479

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.578

Gnomad SAS exome AF: 0.525

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.556 AC: 806606 AN: 1450404 Hom.: 225758 Cov.: 29 AF XY: 0.556 AC XY: 401926 AN XY: 722384

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.507

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.562

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.536 AC: 81371 AN: 151862 Hom.: 21992 Cov.: 31 AF XY: 0.538 AC XY: 39897 AN XY: 74212

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.560

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.514

Alfa AF: 0.544 Hom.: 16057

Bravo AF: 0.531

TwinsUK AF: 0.566 AC: 2099

ALSPAC AF: 0.567 AC: 2184

ESP6500AA AF: 0.486 AC: 2143

ESP6500EA AF: 0.551 AC: 4738

ExAC AF: 0.546 AC: 66308

EpiCase AF: 0.563

EpiControl AF: 0.561

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

PADI4-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

Rheumatoid arthritis;C5441745:Abnormal pulmonary interstitial morphology Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Benign	0.86
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	0.016
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.000097	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.29	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Benign	0.087
Sift	Benign	0.82	T;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.64	.;P
Vest4		0.081
MPC		0.14
ClinPred		0.031	T
GERP RS		4.7
Varity_R		0.42
gMVP		0.29

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: rs874881; hg19: chr1-17660499; COSMIC: COSV64923062;