1-17267867-G-C

Variant names:

• chr1-17267867-G-C
• rs199553716
• NM_016233.2:c.557G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016233.2(PADI3):​c.557G>C​(p.Arg186Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.51

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI3	NM_016233.2	c.557G>C	p.Arg186Pro	missense_variant	Exon 6 of 16	ENST00000375460.3	NP_057317.2
PADI3	XM_011541571.3	c.443G>C	p.Arg148Pro	missense_variant	Exon 6 of 16		XP_011539873.1
PADI3	XM_017001463.2	c.20G>C	p.Arg7Pro	missense_variant	Exon 3 of 13		XP_016856952.1
PADI3	XM_011541572.3	c.557G>C	p.Arg186Pro	missense_variant	Exon 6 of 12		XP_011539874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI3	ENST00000375460.3	c.557G>C	p.Arg186Pro	missense_variant	Exon 6 of 16	1	NM_016233.2	ENSP00000364609.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557G>C (p.R186P) alteration is located in exon 6 (coding exon 6) of the PADI3 gene. This alteration results from a G to C substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a proline (P). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.039	D
Polyphen		0.98	D
Vest4		0.87
MutPred		0.59		Gain of glycosylation at T187 (P = 0.0266);
MVP		0.48
MPC		0.61
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.90

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: rs199553716; hg19: chr1-17594362;