1-17373225-G-A

Position:

• chr1-17373225-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_207421.4(PADI6):​c.286G>A​(p.Ala96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: PADI6 NM_207421.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.739

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006461054).
• BP6: Variant 1-17373225-G-A is Benign according to our data. Variant chr1-17373225-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1176184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000972 (148/152330) while in subpopulation NFE AF= 0.00179 (122/68032). AF 95% confidence interval is 0.00153. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PADI6	NM_207421.4	c.286G>A	p.Ala96Thr	missense_variant	2/16	ENST00000619609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PADI6	ENST00000619609.1	c.286G>A	p.Ala96Thr	missense_variant	2/16	1	NM_207421.4	P1

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00102 AC: 254 AN: 248900 Hom.: 0 AF XY: 0.00115 AC XY: 155 AN XY: 135024

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000883

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00105 AC: 1538 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.00107 AC XY: 779 AN XY: 727102

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74490

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.000744

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.00123 AC: 149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PADI6: BP4 -

PADI6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.64
DEOGEN2	Benign	0.0079	T
FATHMM_MKL	Benign	0.087	N
MetaRNN	Benign	0.0065	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.22	T
Sift4G	Uncertain	0.023	D
Vest4		0.058
MVP		0.13
GERP RS		1.3
Varity_R		0.022
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs181841908; hg19: chr1-17699720;