rs142129409

Variant names:

• chr1-17262194-T-A
• rs142129409
• NM_016233.2:c.335T>A
• PADI3 p.Leu112His

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 12P and 3B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2_Supporting

The NM_016233.2(PADI3):​c.335T>A​(p.Leu112His) variant causes a missense change. The variant allele was found at a frequency of 0.00699 in 1,608,134 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001142291: Functional studies demonstrate that c.335T>A has affected transglutaminase activity of TGM3 produced in HEK293T cells (PMID:27866708)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (38 hom.)
• Consequence: PADI3 NM_016233.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 4.42
• 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: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• uncombable hair syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001142291: Functional studies demonstrate that c.335T>A has affected transglutaminase activity of TGM3 produced in HEK293T cells (PMID: 27866708).; SCV001983056: Published functional studies demonstrate a damaging effect; specifically, the L112H variant is associated with absent enzyme activity and abnormal enzyme aggregation (PMID: 27866708)
• PP5: Variant 1-17262194-T-A is Pathogenic according to our data. Variant chr1-17262194-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03680539). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00721 (10500/1455906) while in subpopulation NFE AF = 0.00846 (9391/1110106). AF 95% confidence interval is 0.00832. There are 38 homozygotes in GnomAdExome4. There are 4993 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.335T>A	p.Leu112His	missense	Exon 3 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.335T>A	p.Leu112His	missense	Exon 3 of 16	ENSP00000364609.3	Q9ULW8

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 744 AN: 152110 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00455 AC: 1108 AN: 243658 AF XY: 0.00439

Gnomad AFR exome AF: 0.000815

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00721 AC: 10500 AN: 1455906 Hom.: 38 Cov.: 30 AF XY: 0.00689 AC XY: 4993 AN XY: 724364

African (AFR) AF: 0.000998 AC: 33 AN: 33066

American (AMR) AF: 0.00414 AC: 178 AN: 42994

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 182 AN: 26010

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39434

South Asian (SAS) AF: 0.00106 AC: 90 AN: 85020

European-Finnish (FIN) AF: 0.00341 AC: 182 AN: 53382

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5762

European-Non Finnish (NFE) AF: 0.00846 AC: 9391 AN: 1110106

Other (OTH) AF: 0.00679 AC: 408 AN: 60132

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152228 Hom.: 3 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74440

African (AFR) AF: 0.00132 AC: 55 AN: 41538

American (AMR) AF: 0.00733 AC: 112 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68016

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00741 Hom.: 6

Bravo AF: 0.00540

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00835

EpiControl AF: 0.00630

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Uncombable hair syndrome 1 (8)
6	-	-	not provided (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	PADI3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.97
gMVP		0.66
Mutation Taster		=31/69	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs142129409;

hg19: chr1-17588689;