chr1-17259627-G-A

Position:

• chr1-17259627-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The ENST00000375460.3(PADI3):​c.142G>A​(p.Val48Met) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,613,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: PADI3 ENST00000375460.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06015539).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI3	NM_016233.2	c.142G>A	p.Val48Met	missense_variant	2/16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3	c.28G>A	p.Val10Met	missense_variant	2/16		XP_011539873.1
PADI3	XM_011541572.3	c.142G>A	p.Val48Met	missense_variant	2/12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3	c.142G>A	p.Val48Met	missense_variant	2/16	1	NM_016233.2	ENSP00000364609	P1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000395 AC: 99 AN: 250630 Hom.: 0 AF XY: 0.000406 AC XY: 55 AN XY: 135414

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 236 AN: 1461056 Hom.: 2 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 726784

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74510

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.000948

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.142G>A (p.V48M) alteration is located in exon 2 (coding exon 2) of the PADI3 gene. This alteration results from a G to A substitution at nucleotide position 142, causing the valine (V) at amino acid position 48 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.44
MPC		0.52
ClinPred		0.069	T
GERP RS		5.2
Varity_R		0.83
gMVP		0.43

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: rs150695491; hg19: chr1-17586122;