1-17333979-G-A

Variant names:

• chr1-17333979-G-A
• rs138247576
• NM_012387.3:c.310G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012387.3(PADI4):​c.310G>A​(p.Val104Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.334
• Publications: 1 publications found

Genes affected

PADI4 (HGNC:18368): (peptidyl arginine deiminase 4) This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine residues to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026985705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3	c.310G>A	p.Val104Ile	missense_variant	Exon 3 of 16	ENST00000375448.4	NP_036519.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI4	ENST00000375448.4	c.310G>A	p.Val104Ile	missense_variant	Exon 3 of 16	1	NM_012387.3	ENSP00000364597.4
PADI4	ENST00000375453.5	c.310G>A	p.Val104Ile	missense_variant	Exon 3 of 4	2		ENSP00000364602.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152126 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000290 AC: 73 AN: 251460 AF XY: 0.000243

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000496 AC: 724 AN: 1460842 Hom.: 0 Cov.: 29 AF XY: 0.000476 AC XY: 346 AN XY: 726812

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000590 AC: 656 AN: 1111054

Other (OTH) AF: 0.000646 AC: 39 AN: 60364

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152244 Hom.: 0 Cov.: 30 AF XY: 0.000228 AC XY: 17 AN XY: 74442

African (AFR) AF: 0.000144 AC: 6 AN: 41550

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000401 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310G>A (p.V104I) alteration is located in exon 3 (coding exon 3) of the PADI4 gene. This alteration results from a G to A substitution at nucleotide position 310, causing the valine (V) at amino acid position 104 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0084	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;M
PhyloP100		0.33
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.054
Sift	Benign	0.54	T;T
Sift4G	Uncertain	0.042	D;T
Polyphen		0.14	.;B
Vest4		0.093
MVP		0.061
MPC		0.094
ClinPred		0.026	T
GERP RS		0.29
Varity_R		0.19
gMVP		0.094
Mutation Taster		=83/17	polymorphism

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: rs138247576; hg19: chr1-17660474;