rs12733102

chr1-17336210-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_012387.3(PADI4):c.392G>C(p.Arg131Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,548 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 33)
  • Exomes 𝑓: 0.022 (418 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033593178).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2436/152282) while in subpopulation NFE AF= 0.0244 (1661/68030). AF 95% confidence interval is 0.0234. There are 34 homozygotes in gnomad4. There are 1123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI4	NM_012387.3	c.392G>C	p.Arg131Thr	missense_variant	4/16	ENST00000375448.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI4	ENST00000375448.4	c.392G>C	p.Arg131Thr	missense_variant	4/16	1	NM_012387.3	P1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2432 AN: 152164 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0163 AC: 4087 AN: 251338 Hom.: 60 AF XY: 0.0168 AC XY: 2283 AN XY: 135860

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00926

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0218 AC: 31784 AN: 1461266 Hom.: 418 Cov.: 33 AF XY: 0.0216 AC XY: 15681 AN XY: 726990

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.00995

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00979

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.0246

Gnomad4 OTH exome AF: 0.0216

GnomAD4 genome AF: 0.0160 AC: 2436 AN: 152282 Hom.: 34 Cov.: 33 AF XY: 0.0151 AC XY: 1123 AN XY: 74450

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0234 Hom.: 41

Bravo AF: 0.0157

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0160 AC: 1940

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	10
Dann	Benign	0.81
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.094	N
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.069
Sift	Benign	0.26	T
Sift4G	Benign	0.42	T
Polyphen		0.64	P
Vest4		0.062
MPC		0.30
ClinPred		0.011	T
GERP RS		-3.5
Varity_R		0.052
gMVP		0.14

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: rs12733102; hg19: chr1-17662705;