1-17270243-T-G

Variant summary

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

The NM_016233.2(PADI3):c.663T>G(p.Asp221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,610,262 control chromosomes in the GnomAD database, including 14 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (13 hom.)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.691

Genes affected

PADI3 (HGNC:18337): (peptidyl arginine deiminase 3) This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type III enzyme modulates hair structural proteins, such as filaggrin in the hair follicle and trichohyalin in the inner root sheath, during hair follicle formation. Together with the type I enzyme, this enzyme may also play a role in terminal differentiation of the epidermis. This gene exists in a cluster with four other paralogous genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005556166).
• BP6: Variant 1-17270243-T-G is Benign according to our data. Variant chr1-17270243-T-G is described in ClinVar as [Benign]. Clinvar id is 3037611.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000555 (809/1458402) while in subpopulation AMR AF= 0.0163 (723/44344). AF 95% confidence interval is 0.0153. There are 13 homozygotes in gnomad4_exome. There are 334 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI3	NM_016233.2	c.663T>G	p.Asp221Glu	missense_variant	7/16	ENST00000375460.3
PADI3	XM_011541571.3	c.549T>G	p.Asp183Glu	missense_variant	7/16
PADI3	XM_017001463.2	c.126T>G	p.Asp42Glu	missense_variant	4/13
PADI3	XM_011541572.3	c.663T>G	p.Asp221Glu	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI3	ENST00000375460.3	c.663T>G	p.Asp221Glu	missense_variant	7/16	1	NM_016233.2	P1

Frequencies

GnomAD3 genomes AF: 0.000751 AC: 114 AN: 151742 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00571

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00253 AC: 626 AN: 247672 Hom.: 12 AF XY: 0.00186 AC XY: 249 AN XY: 133846

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000659

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000555 AC: 809 AN: 1458402 Hom.: 13 Cov.: 31 AF XY: 0.000460 AC XY: 334 AN XY: 725492

Gnomad4 AFR exome AF: 0.000421

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000531

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.000751 AC: 114 AN: 151860 Hom.: 1 Cov.: 31 AF XY: 0.000633 AC XY: 47 AN XY: 74202

Gnomad4 AFR AF: 0.000435

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.0000697 Hom.: 0

Bravo AF: 0.00192

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PADI3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2020

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	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	10
Dann	Benign	0.96
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.43	N
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.22
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.89	P
Vest4		0.54
MutPred		0.41		Loss of sheet (P = 0.0817);
MVP		0.28
MPC		0.23
ClinPred		0.012	T
GERP RS		2.8
Varity_R		0.047
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145276833; hg19: chr1-17596738;