Genetic Variant NM_012387.3:c.98C>A (chr1-17330974-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12

Publications

0 publications found

Variant links:

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]

PADI4 links:

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ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3 link	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 16	ENST00000375448.4	NP_036519.2	Q9UM07

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI4	ENST00000375448.4 link	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 16	1	NM_012387.3	ENSP00000364597.4		Q9UM07
PADI4	ENST00000375453.5 link	c.98C>A	p.Ala33Asp	missense_variant	Exon 2 of 4	2		ENSP00000364602.1		B1AQ67

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.06e-7

AC:

AN:

1417156

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704098

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30772

American (AMR)

AF:

0.00

AC:

AN:

34740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24208

East Asian (EAS)

AF:

0.00

AC:

AN:

36884

South Asian (SAS)

AF:

0.00

AC:

AN:

79512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1093832

Other (OTH)

AF:

0.00

AC:

AN:

58598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

3.1

.;M

PhyloP100

4.1

PrimateAI

Uncertain

0.48

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

GERP RS

5.3

Varity_R

0.96

gMVP

0.72

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over