rs11203367

chr1-17331121-T-C

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.245T>C(p.Val82Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,610,008 control chromosomes in the GnomAD database, including 268,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (23863 hom., cov: 33)
  • Exomes 𝑓: 0.58 (244442 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.25

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=5.8372883E-5).
• BP6: Variant 1-17331121-T-C is Benign according to our data. Variant chr1-17331121-T-C is described in ClinVar as [Benign]. Clinvar id is 972893.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI4	NM_012387.3	c.245T>C	p.Val82Ala	missense_variant	2/16	ENST00000375448.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI4	ENST00000375448.4	c.245T>C	p.Val82Ala	missense_variant	2/16	1	NM_012387.3	P1
PADI4	ENST00000375453.5	c.245T>C	p.Val82Ala	missense_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84813 AN: 151922 Hom.: 23868 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.581

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.537

GnomAD3 exomes AF: 0.562 AC: 139062 AN: 247580 Hom.: 39496 AF XY: 0.565 AC XY: 75670 AN XY: 133914

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.596

Gnomad EAS exome AF: 0.578

Gnomad SAS exome AF: 0.527

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.574

GnomAD4 exome AF: 0.578 AC: 842352 AN: 1457968 Hom.: 244442 Cov.: 45 AF XY: 0.577 AC XY: 418665 AN XY: 725250

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.533

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.558 AC: 84845 AN: 152040 Hom.: 23863 Cov.: 33 AF XY: 0.558 AC XY: 41491 AN XY: 74296

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.551

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.593

Gnomad4 NFE AF: 0.584

Gnomad4 OTH AF: 0.530

Alfa AF: 0.579 Hom.: 55324

Bravo AF: 0.552

TwinsUK AF: 0.587 AC: 2176

ALSPAC AF: 0.591 AC: 2278

ESP6500AA AF: 0.509 AC: 2242

ESP6500EA AF: 0.576 AC: 4957

ExAC AF: 0.564 AC: 68425

Asia WGS AF: 0.488 AC: 1698 AN: 3478

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	0.053
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.6
Dann	Benign	0.26
DEOGEN2	Benign	0.0048	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00064	N
MetaRNN	Benign	0.000058	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.018
MPC		0.13
ClinPred		0.0022	T
GERP RS		4.7
Varity_R		0.052
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11203367; hg19: chr1-17657616; COSMIC: COSV64923414;