1-17266815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_016233.2(PADI3):​c.505C>T​(p.Gln169*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,892 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

PADI3
NM_016233.2 stop_gained

Scores

3
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.386
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-17266815-C-T is Pathogenic according to our data. Variant chr1-17266815-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3602987.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PADI3NM_016233.2 linkc.505C>T p.Gln169* stop_gained Exon 5 of 16 ENST00000375460.3 NP_057317.2
PADI3XM_011541571.3 linkc.391C>T p.Gln131* stop_gained Exon 5 of 16 XP_011539873.1
PADI3XM_011541572.3 linkc.505C>T p.Gln169* stop_gained Exon 5 of 12 XP_011539874.1
PADI3XM_017001463.2 linkc.-33C>T 5_prime_UTR_variant Exon 2 of 13 XP_016856952.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PADI3ENST00000375460.3 linkc.505C>T p.Gln169* stop_gained Exon 5 of 16 1 NM_016233.2 ENSP00000364609.3 Q9ULW8

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000151
AC:
38
AN:
251304
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135824
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000282
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000115
AC:
168
AN:
1461634
Hom.:
1
Cov.:
31
AF XY:
0.000127
AC XY:
92
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000131
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000253
Hom.:
0
Bravo
AF:
0.000189
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000273
EpiControl
AF:
0.000474

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Aug 06, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 36044230, 31345219) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.11
N
Vest4
0.10
GERP RS
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199615967; hg19: chr1-17593310; COSMIC: COSV64935562; API