NM_012387.3:c.335G>C

Variant names:

• chr1-17334004-G-C
• rs874881
• NM_012387.3:c.335G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,association (no stars).

• Frequency:
  • Genomes: 𝑓 0.54 (21992 hom., cov: 31)
  • Exomes 𝑓: 0.56 (225758 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign; association no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 3.69
• Publications: 94 publications found

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

Our verdict: Benign. The variant received -13 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|association. ClinVar VariationId is 972895.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012387.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI4	NM_012387.3	MANE Select	c.335G>C	p.Gly112Ala	missense	Exon 3 of 16	NP_036519.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI4	ENST00000375448.4	TSL:1 MANE Select	c.335G>C	p.Gly112Ala	missense	Exon 3 of 16	ENSP00000364597.4
	PADI4	ENST00000375453.5	TSL:2	c.335G>C	p.Gly112Ala	missense	Exon 3 of 4	ENSP00000364602.1

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

GnomAD2 exomes AF: 0.545 AC: 136995 AN: 251246 AF XY: 0.549

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 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

African (AFR) AF: 0.476 AC: 15818 AN: 33252

American (AMR) AF: 0.507 AC: 22659 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15161 AN: 26052

East Asian (EAS) AF: 0.592 AC: 23470 AN: 39626

South Asian (SAS) AF: 0.530 AC: 45604 AN: 86042

European-Finnish (FIN) AF: 0.555 AC: 29594 AN: 53356

Middle Eastern (MID) AF: 0.559 AC: 3211 AN: 5746

European-Non Finnish (NFE) AF: 0.562 AC: 618607 AN: 1101616

Other (OTH) AF: 0.541 AC: 32482 AN: 60024

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

African (AFR) AF: 0.479 AC: 19842 AN: 41406

American (AMR) AF: 0.539 AC: 8215 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2073 AN: 3462

East Asian (EAS) AF: 0.590 AC: 3024 AN: 5124

South Asian (SAS) AF: 0.533 AC: 2567 AN: 4812

European-Finnish (FIN) AF: 0.560 AC: 5911 AN: 10550

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37909 AN: 67956

Other (OTH) AF: 0.514 AC: 1081 AN: 2104

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; association

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

PADI4-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 2020

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.016
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.000097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.7
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.087
Sift	Benign	0.82	T
Sift4G	Pathogenic	0.0	D
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
Mutation Taster		=68/32	polymorphism (auto)

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

Other links and lift over

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