chr1-17331097-T-C

Variant names:

• chr1-17331097-T-C
• rs57969340
• NM_012387.3:c.221T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012387.3(PADI4):​c.221T>C​(p.Val74Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,612,070 control chromosomes in the GnomAD database, including 18 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. V74L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (11 hom.)
• Consequence: PADI4 NM_012387.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.21
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008436352).
• BP6: Variant 1-17331097-T-C is Benign according to our data. Variant chr1-17331097-T-C is described in ClinVar as Benign. ClinVar VariationId is 711266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00607 (924/152120) while in subpopulation AFR AF = 0.0201 (836/41496). AF 95% confidence interval is 0.019. There are 7 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.221T>C	p.Val74Ala	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.221T>C	p.Val74Ala	missense	Exon 2 of 16	ENSP00000364597.4	Q9UM07
	PADI4	ENST00000375453.5	TSL:2	c.221T>C	p.Val74Ala	missense	Exon 2 of 4	ENSP00000364602.1	B1AQ67

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 925 AN: 152002 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00163 AC: 405 AN: 249002 AF XY: 0.00130

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000593 AC: 866 AN: 1459950 Hom.: 11 Cov.: 37 AF XY: 0.000509 AC XY: 370 AN XY: 726230

African (AFR) AF: 0.0190 AC: 635 AN: 33376

American (AMR) AF: 0.00169 AC: 75 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111156

Other (OTH) AF: 0.00148 AC: 89 AN: 60338

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152120 Hom.: 7 Cov.: 33 AF XY: 0.00605 AC XY: 450 AN XY: 74372

African (AFR) AF: 0.0201 AC: 836 AN: 41496

American (AMR) AF: 0.00419 AC: 64 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00685

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.0037
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		4.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Uncertain	0.022	D
Polyphen		0.63	P
Vest4		0.22
MVP		0.31
MPC		0.29
ClinPred		0.041	T
GERP RS		5.6
Varity_R		0.33
gMVP		0.20
Mutation Taster		=96/4	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: rs57969340; hg19: chr1-17657592;