22-24734100-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001255975.1(PIWIL3):c.1691G>T(p.Arg564Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07246956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1691G>T	p.Arg564Ile	missense_variant	14/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.1691G>T	p.Arg564Ile	missense_variant	14/21
PIWIL3	NR_045648.1	n.2322G>T		non_coding_transcript_exon_variant	15/22
PIWIL3	NR_045649.2	n.2195G>T		non_coding_transcript_exon_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1691G>T	p.Arg564Ile	missense_variant	14/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.1691G>T	p.Arg564Ile	missense_variant	14/21	1		P2
PIWIL3	ENST00000527701.6	c.*1663G>T		3_prime_UTR_variant, NMD_transcript_variant	15/22	1
PIWIL3	ENST00000533313.6	c.*1617G>T		3_prime_UTR_variant, NMD_transcript_variant	15/22	1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249590 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1459938 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.1691G>T (p.R564I) alteration is located in exon 14 (coding exon 13) of the PIWIL3 gene. This alteration results from a G to T substitution at nucleotide position 1691, causing the arginine (R) at amino acid position 564 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.0
Dann	Benign	0.82
DEOGEN2	Benign	0.015	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.62	T;.;.;T
M_CAP	Benign	0.00058	T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.014	B;B;B;B
Vest4		0.25
MutPred		0.48		Loss of MoRF binding (P = 0.0723);Loss of MoRF binding (P = 0.0723);.;.;
MVP		0.22
MPC		0.20
ClinPred		0.027	T
GERP RS		-0.82
Varity_R		0.060
gMVP		0.16

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: rs912648757; hg19: chr22-25130067;