chr1-17330974-C-A

Variant names:

• chr1-17330974-C-A
• NM_012387.3:c.98C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012387.3(PADI4):​c.98C>A​(p.Ala33Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,417,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 16	ENST00000375448.4	NP_036519.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI4	ENST00000375448.4	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 16	1	NM_012387.3	ENSP00000364597.4
PADI4	ENST00000375453.5	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 4	2		ENSP00000364602.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417156 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 704098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98C>A (p.A33D) alteration is located in exon 2 (coding exon 2) of the PADI4 gene. This alteration results from a C to A substitution at nucleotide position 98, causing the alanine (A) at amino acid position 33 to be replaced by an aspartic acid (D). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.76
MutPred		0.76		Gain of disorder (P = 0.0442);Gain of disorder (P = 0.0442);
MVP		0.42
MPC		0.65
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-17657469;