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. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. 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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI4	NM_012387.3	c.236C>T	p.Thr79Met	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.236C>T	p.Thr79Met	missense_variant	Exon 2 of 16	1	NM_012387.3	ENSP00000364597.4
PADI4	ENST00000375453.5	c.236C>T	p.Thr79Met	missense_variant	Exon 2 of 4	2		ENSP00000364602.1

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

GnomAD3 exomes AF: 0.00417 AC: 1036 AN: 248398 Hom.: 26 AF XY: 0.00305 AC XY: 409 AN XY: 134292

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 SAS exome AF: 0.000165

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

Gnomad4 AFR exome AF: 0.0583

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00350

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

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.00792

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00494 Hom.: 6

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0095	N
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.077
Sift	Benign	0.12	T;T
Sift4G	Benign	0.074	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs35809521; hg19: chr1-17657607; COSMIC: COSV64923941;