chr1-17308245-G-A

Position:

• chr1-17308245-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000375448.4(PADI4):​c.23G>A​(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,614,030 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (103 hom.)
• Consequence: PADI4 ENST00000375448.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.32

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003020823).
• BP6: Variant 1-17308245-G-A is Benign according to our data. Variant chr1-17308245-G-A is described in ClinVar as [Benign]. Clinvar id is 777323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI4	NM_012387.3	c.23G>A	p.Arg8His	missense_variant	1/16	ENST00000375448.4	NP_036519.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI4	ENST00000375448.4	c.23G>A	p.Arg8His	missense_variant	1/16	1	NM_012387.3	ENSP00000364597	P1
PADI4	ENST00000375453.5	c.23G>A	p.Arg8His	missense_variant	1/4	2		ENSP00000364602

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3163 AN: 152158 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00563 AC: 1414 AN: 251228 Hom.: 44 AF XY: 0.00421 AC XY: 572 AN XY: 135780

Gnomad AFR exome AF: 0.0727

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00227 AC: 3321 AN: 1461754 Hom.: 103 Cov.: 30 AF XY: 0.00204 AC XY: 1482 AN XY: 727180

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.0208 AC: 3172 AN: 152276 Hom.: 105 Cov.: 32 AF XY: 0.0203 AC XY: 1511 AN XY: 74468

Gnomad4 AFR AF: 0.0705

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00763 Hom.: 38

Bravo AF: 0.0235

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00687 AC: 834

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -

PADI4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.30	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.026
Sift	Benign	0.19	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.024	.;B
Vest4		0.16
MVP		0.067
MPC		0.14
ClinPred		0.0061	T
GERP RS		1.9
Varity_R		0.16
gMVP		0.23

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: rs35381732; hg19: chr1-17634740;