Genetic Variant PADI4:p.Ser275Phe (chr1-17342114-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012387.3(PADI4):c.824C>T(p.Ser275Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,613,608 control chromosomes in the GnomAD database, including 2,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.060 ( 335 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2132 hom. )

Consequence

PADI4
NM_012387.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.113

Publications

20 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002763629).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3 link	c.824C>T	p.Ser275Phe	missense_variant	Exon 7 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.824C>T	p.Ser275Phe	missense_variant	Exon 7 of 16	1	NM_012387.3	ENSP00000364597.4		Q9UM07

Frequencies

GnomAD3 genomes

AF:

0.0604

AC:

9187

AN:

152142

Hom.:

332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0971

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0542

Gnomad OTH

AF:

0.0455

GnomAD2 exomes

AF:

0.0425

AC:

10686

AN:

251166

AF XY:

0.0414

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.0149

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.000816

Gnomad FIN exome

AF:

0.0581

Gnomad NFE exome

AF:

0.0533

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0502

AC:

73410

AN:

1461348

Hom.:

2132

Cov.:

AF XY:

0.0491

AC XY:

35686

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.0996

AC:

3334

AN:

33468

American (AMR)

AF:

0.0163

AC:

727

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

894

AN:

26120

East Asian (EAS)

AF:

0.000730

AC:

AN:

39700

South Asian (SAS)

AF:

0.0213

AC:

1835

AN:

86246

European-Finnish (FIN)

AF:

0.0593

AC:

3167

AN:

53406

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.0544

AC:

60504

AN:

1111722

Other (OTH)

AF:

0.0472

AC:

2848

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3618

7236

10855

14473

18091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2216

4432

6648

8864

11080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0604

AC:

9197

AN:

152260

Hom.:

335

Cov.:

AF XY:

0.0589

AC XY:

4385

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0971

AC:

4033

AN:

41540

American (AMR)

AF:

0.0302

AC:

462

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5178

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4824

European-Finnish (FIN)

AF:

0.0596

AC:

633

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0542

AC:

3686

AN:

68018

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

452

904

1356

1808

2260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0518

Hom.:

773

Bravo

AF:

0.0600

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.103

AC:

456

ESP6500EA

AF:

0.0530

AC:

456

ExAC

AF:

0.0456

AC:

5534

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0497

EpiControl

AF:

0.0474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

0.021

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.059

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

-0.11

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.091

Sift

Uncertain

0.025

Sift4G

Benign

0.081

Polyphen

0.92

Vest4

0.30

MPC

0.49

ClinPred

0.038

GERP RS

4.6

Varity_R

0.29

gMVP

0.31

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over