rs3750300

Variant names:

• chr1-17259639-A-G
• rs3750300
• NM_016233.2:c.154A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_016233.2(PADI3):​c.154A>G​(p.Ile52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 1,613,328 control chromosomes in the GnomAD database, including 8,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.093 (698 hom., cov: 33)
  • Exomes 𝑓: 0.098 (7870 hom.)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0130
• Publications: 23 publications found

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]

PADI3 Gene-Disease associations (from GenCC):

• uncombable hair syndrome 1

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• uncombable hair syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002042234).
• BP6: Variant 1-17259639-A-G is Benign according to our data. Variant chr1-17259639-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059385.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016233.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI3	NM_016233.2	MANE Select	c.154A>G	p.Ile52Val	missense	Exon 2 of 16	NP_057317.2	Q9ULW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI3	ENST00000375460.3	TSL:1 MANE Select	c.154A>G	p.Ile52Val	missense	Exon 2 of 16	ENSP00000364609.3	Q9ULW8

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14109 AN: 152144 Hom.: 696 Cov.: 33

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0876

Gnomad OTH AF: 0.0928

GnomAD2 exomes AF: 0.109 AC: 27311 AN: 250788 AF XY: 0.113

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0982 AC: 143513 AN: 1461066 Hom.: 7870 Cov.: 31 AF XY: 0.101 AC XY: 73618 AN XY: 726772

African (AFR) AF: 0.0799 AC: 2671 AN: 33444

American (AMR) AF: 0.127 AC: 5651 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 1580 AN: 26130

East Asian (EAS) AF: 0.157 AC: 6228 AN: 39662

South Asian (SAS) AF: 0.195 AC: 16831 AN: 86116

European-Finnish (FIN) AF: 0.0637 AC: 3400 AN: 53416

Middle Eastern (MID) AF: 0.0904 AC: 521 AN: 5762

European-Non Finnish (NFE) AF: 0.0902 AC: 100264 AN: 1111520

Other (OTH) AF: 0.105 AC: 6367 AN: 60354

GnomAD4 genome AF: 0.0927 AC: 14117 AN: 152262 Hom.: 698 Cov.: 33 AF XY: 0.0941 AC XY: 7008 AN XY: 74452

African (AFR) AF: 0.0821 AC: 3412 AN: 41560

American (AMR) AF: 0.121 AC: 1843 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.158 AC: 815 AN: 5168

South Asian (SAS) AF: 0.198 AC: 954 AN: 4824

European-Finnish (FIN) AF: 0.0639 AC: 678 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0876 AC: 5958 AN: 68018

Other (OTH) AF: 0.0952 AC: 201 AN: 2112

Alfa AF: 0.0911 Hom.: 3405

Bravo AF: 0.0947

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0981 AC: 378

ESP6500AA AF: 0.0833 AC: 367

ESP6500EA AF: 0.0919 AC: 790

ExAC AF: 0.109 AC: 13274

Asia WGS AF: 0.173 AC: 602 AN: 3476

EpiCase AF: 0.0898

EpiControl AF: 0.0932

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PADI3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0080
DANN	Benign	0.43
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.013
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.084
ClinPred		0.0012	T
GERP RS		0.16
Varity_R		0.13
gMVP		0.096
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3750300; hg19: chr1-17586134; COSMIC: COSV64934254;