chr1-17330974-C-A

Variant names:

• chr1-17330974-C-A
• rs1199802826
• NM_012387.3:c.98C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012387.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI4	NM_012387.3	MANE Select	c.98C>A	p.Ala33Asp	missense	Exon 2 of 16	NP_036519.2	Q9UM07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PADI4	ENST00000375448.4	TSL:1 MANE Select	c.98C>A	p.Ala33Asp	missense	Exon 2 of 16	ENSP00000364597.4	Q9UM07
	PADI4	ENST00000375453.5	TSL:2	c.98C>A	p.Ala33Asp	missense	Exon 2 of 4	ENSP00000364602.1	B1AQ67

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30772

American (AMR) AF: 0.00 AC: 0 AN: 34740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 36884

South Asian (SAS) AF: 0.00 AC: 0 AN: 79512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093832

Other (OTH) AF: 0.00 AC: 0 AN: 58598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.76		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
Mutation Taster		=66/34	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: rs1199802826; hg19: chr1-17657469;