22-24719489-G-A

Position:

• chr22-24719489-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001255975.1(PIWIL3):​c.2605C>T​(p.Arg869Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,589,020 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (119 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (128 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.434

Genes affected

PIWIL3 (HGNC:18443): (piwi like RNA-mediated gene silencing 3) This gene encodes a member of the PIWI subfamily of Argonaute family proteins. This subfamily of proteins contains a PAZ domain, found in proteins involved in RNA-mediated gene silencing, and a C-terminal Piwi domain. The encoded protein is thought to function in maintenance of germline cells. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

PIWIL3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038630962).
• BP6: Variant 22-24719489-G-A is Benign according to our data. Variant chr22-24719489-G-A is described in ClinVar as [Benign]. Clinvar id is 782793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIWIL3	NM_001255975.1	c.2605C>T	p.Arg869Cys	missense_variant	21/21	ENST00000616349.5	NP_001242904.1
PIWIL3	NM_001008496.3	c.2632C>T	p.Arg878Cys	missense_variant	21/21		NP_001008496.2
PIWIL3	NR_045648.1	n.3236C>T		non_coding_transcript_exon_variant	22/22
PIWIL3	NR_045649.2	n.3109C>T		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5	c.2605C>T	p.Arg869Cys	missense_variant	21/21	1	NM_001255975.1	ENSP00000479524.2

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3286 AN: 152172 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00613 AC: 1410 AN: 230202 Hom.: 56 AF XY: 0.00434 AC XY: 539 AN XY: 124242

Gnomad AFR exome AF: 0.0783

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00220 AC: 3158 AN: 1436730 Hom.: 128 Cov.: 30 AF XY: 0.00196 AC XY: 1397 AN XY: 713302

Gnomad4 AFR exome AF: 0.0795

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.0000744

Gnomad4 OTH exome AF: 0.00470

GnomAD4 genome AF: 0.0216 AC: 3290 AN: 152290 Hom.: 119 Cov.: 32 AF XY: 0.0210 AC XY: 1564 AN XY: 74460

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00396 Hom.: 30

Bravo AF: 0.0252

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.5
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.62	T;.;.;T
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.3	.;D;D;D
REVEL	Benign	0.039
Sift	Uncertain	0.018	.;D;D;D
Sift4G	Benign	0.094	T;T;T;T
Polyphen		0.88	P;P;D;D
Vest4		0.090
MVP		0.36
MPC		0.15
ClinPred		0.077	T
GERP RS		-5.0
Varity_R		0.11
gMVP		0.21

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: rs61733498; hg19: chr22-25115456;