NM_012387.3:c.236C>T

Variant names:

• chr1-17331112-C-T
• rs35809521
• NM_012387.3:c.236C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012387.3(PADI4):​c.236C>T​(p.Thr79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,611,938 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T79R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (60 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.65
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037055612).
• BP6: Variant 1-17331112-C-T is Benign according to our data. Variant chr1-17331112-C-T is described in ClinVar as Benign. ClinVar VariationId is 780217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

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.236C>T	p.Thr79Met	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.236C>T	p.Thr79Met	missense	Exon 2 of 16	ENSP00000364597.4	Q9UM07
	PADI4	ENST00000375453.5	TSL:2	c.236C>T	p.Thr79Met	missense	Exon 2 of 4	ENSP00000364602.1	B1AQ67

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2488 AN: 152134 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00793

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00417 AC: 1036 AN: 248398 AF XY: 0.00305

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00168 AC: 2452 AN: 1459686 Hom.: 60 Cov.: 37 AF XY: 0.00144 AC XY: 1042 AN XY: 726100

African (AFR) AF: 0.0583 AC: 1941 AN: 33304

American (AMR) AF: 0.00280 AC: 124 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39544

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85886

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53394

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111112

Other (OTH) AF: 0.00350 AC: 211 AN: 60330

GnomAD4 genome AF: 0.0164 AC: 2490 AN: 152252 Hom.: 61 Cov.: 33 AF XY: 0.0154 AC XY: 1145 AN XY: 74430

African (AFR) AF: 0.0558 AC: 2317 AN: 41546

American (AMR) AF: 0.00792 AC: 121 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00585 Hom.: 9

Bravo AF: 0.0184

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0554 AC: 244

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00525 AC: 637

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0095	N
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.077
Sift	Benign	0.12	T
Sift4G	Benign	0.074	T
Polyphen		0.99	D
Vest4		0.12
MVP		0.076
MPC		0.12
ClinPred		0.025	T
GERP RS		-10
Varity_R		0.046
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35809521; hg19: chr1-17657607; COSMIC: COSV64923941;