1-17381046-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3_ModeratePP5

The NM_207421.4(PADI6):​c.441dup​(p.Trp148MetfsTer20) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,592,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PADI6
NM_207421.4 frameshift, splice_region

Scores

Not classified

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.803
Variant links:
Genes affected
PADI6 (HGNC:20449): (peptidyl arginine deiminase 6) 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. This protein may play a role in cytoskeletal reorganization in the egg and in early embryo development. [provided by RefSeq, Sep 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-17381046-G-GA is Pathogenic according to our data. Variant chr1-17381046-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2633287.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PADI6NM_207421.4 linkuse as main transcriptc.441dup p.Trp148MetfsTer20 frameshift_variant, splice_region_variant ENST00000619609.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PADI6ENST00000619609.1 linkuse as main transcriptc.441dup p.Trp148MetfsTer20 frameshift_variant, splice_region_variant 1 NM_207421.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000928
AC:
2
AN:
215506
Hom.:
0
AF XY:
0.0000172
AC XY:
2
AN XY:
116350
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000330
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000104
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000625
AC:
9
AN:
1440148
Hom.:
0
Cov.:
30
AF XY:
0.00000700
AC XY:
5
AN XY:
714436
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000731
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000545
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

PADI6-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 29, 2024The PADI6 c.441dupA variant is predicted to result in a frameshift and premature protein termination (p.Trp148Metfs*20). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0032% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PADI6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.93
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.91
Position offset: 0
DS_AL_spliceai
0.93
Position offset: 1

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: rs1275178104; hg19: chr1-17707541; API