1-17373219-G-T

Variant names:

• chr1-17373219-G-T
• rs200488264
• NM_207421.4:c.280G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_207421.4(PADI6):​c.280G>T​(p.Val94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V94M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: PADI6 NM_207421.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.42

Genes affected

PADI6 (HGNC:20449): (peptidyl arginine deiminase 6) This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. This protein may play a role in cytoskeletal reorganization in the egg and in early embryo development. [provided by RefSeq, Sep 2012]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008853823).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (154/152272) while in subpopulation NFE AF = 0.00191 (130/68024). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI6	NM_207421.4	c.280G>T	p.Val94Leu	missense_variant	Exon 2 of 16	ENST00000619609.1	NP_997304.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PADI6	ENST00000619609.1	c.280G>T	p.Val94Leu	missense_variant	Exon 2 of 16	1	NM_207421.4	ENSP00000483125.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000791 AC: 197 AN: 248974 AF XY: 0.000770

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00136 AC: 1991 AN: 1461626 Hom.: 2 Cov.: 31 AF XY: 0.00132 AC XY: 959 AN XY: 727110

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33480

Gnomad4 AMR exome AF: 0.000224 AC: 10 AN: 44718

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.000449 AC: 24 AN: 53396

Gnomad4 NFE exome AF: 0.00171 AC: 1902 AN: 1111820

Gnomad4 Remaining exome AF: 0.000745 AC: 45 AN: 60370

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74446

Gnomad4 AFR AF: 0.000265 AC: 0.000264627 AN: 0.000264627

Gnomad4 AMR AF: 0.000589 AC: 0.000588774 AN: 0.000588774

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000283 AC: 0.000282592 AN: 0.000282592

Gnomad4 NFE AF: 0.00191 AC: 0.00191109 AN: 0.00191109

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.00188 AC: 16

ExAC AF: 0.000751 AC: 91

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280G>T (p.V94L) alteration is located in exon 2 (coding exon 2) of the PADI6 gene. This alteration results from a G to T substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0020
DANN	Benign	0.65
DEOGEN2	Benign	0.0052	T
FATHMM_MKL	Benign	0.040	N
MetaRNN	Benign	0.0089	T
MutationAssessor	Benign	0.76	N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.77	T
Vest4		0.070
MVP		0.061
GERP RS		-6.5
Varity_R		0.030
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs200488264; hg19: chr1-17699714; COSMIC: COSV61884109;