chr1-17333973-C-A

Variant names:

• chr1-17333973-C-A
• rs34309058
• NM_012387.3:c.304C>A

Variant summary

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

The NM_012387.3(PADI4):​c.304C>A​(p.Pro102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,612,530 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 30)
  • Exomes 𝑓: 0.015 (225 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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=0.0029465556).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1666/152240) while in subpopulation NFE AF= 0.0173 (1178/68010). AF 95% confidence interval is 0.0165. There are 16 homozygotes in gnomad4. There are 780 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3	c.304C>A	p.Pro102Thr	missense_variant	Exon 3 of 16	ENST00000375448.4	NP_036519.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI4	ENST00000375448.4	c.304C>A	p.Pro102Thr	missense_variant	Exon 3 of 16	1	NM_012387.3	ENSP00000364597.4
PADI4	ENST00000375453.5	c.304C>A	p.Pro102Thr	missense_variant	Exon 3 of 4	2		ENSP00000364602.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1666 AN: 152122 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0108 AC: 2715 AN: 251444 Hom.: 25 AF XY: 0.0109 AC XY: 1482 AN XY: 135898

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0153 AC: 22337 AN: 1460290 Hom.: 225 Cov.: 28 AF XY: 0.0149 AC XY: 10800 AN XY: 726548

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.00754

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0109 AC: 1666 AN: 152240 Hom.: 16 Cov.: 30 AF XY: 0.0105 AC XY: 780 AN XY: 74432

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0145 Hom.: 37

Bravo AF: 0.0112

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0106 AC: 1283

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0183

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.5
DANN	Benign	0.85
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0047	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.010
Sift	Benign	0.093	T;D
Sift4G	Benign	0.79	T;T
Polyphen		0.0060	.;B
Vest4		0.12
MPC		0.12
ClinPred		0.0099	T
GERP RS		-9.5
Varity_R		0.10
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34309058; hg19: chr1-17660468; COSMIC: COSV99080970;