rs11588132

chr1-17338120-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012387.3(PADI4):c.491T>C(p.Met164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,612,974 control chromosomes in the GnomAD database, including 13 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M164I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.553

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=0.008557886).
• BP6: Variant 1-17338120-T-C is Benign according to our data. Variant chr1-17338120-T-C is described in ClinVar as [Benign]. Clinvar id is 3044642.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000503 (735/1460706) while in subpopulation AFR AF= 0.0173 (579/33442). AF 95% confidence interval is 0.0161. There are 7 homozygotes in gnomad4_exome. There are 321 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI4	NM_012387.3	c.491T>C	p.Met164Thr	missense_variant	5/16	ENST00000375448.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI4	ENST00000375448.4	c.491T>C	p.Met164Thr	missense_variant	5/16	1	NM_012387.3	P1

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 699 AN: 152150 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00117 AC: 294 AN: 251472 Hom.: 2 AF XY: 0.000942 AC XY: 128 AN XY: 135910

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000503 AC: 735 AN: 1460706 Hom.: 7 Cov.: 29 AF XY: 0.000442 AC XY: 321 AN XY: 726690

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152268 Hom.: 6 Cov.: 32 AF XY: 0.00446 AC XY: 332 AN XY: 74462

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000766 Hom.: 1

Bravo AF: 0.00544

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PADI4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 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	0.081
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.1
Dann	Benign	0.31
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.49	N
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.015
Sift	Benign	0.53	T
Sift4G	Benign	0.58	T
Polyphen		0.22	B
Vest4		0.082
MVP		0.21
MPC		0.13
ClinPred		0.0012	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.17

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: rs11588132; hg19: chr1-17664615; COSMIC: COSV99080966; COSMIC: COSV99080966;