22-24723193-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001255975.1(PIWIL3):c.2294G>A(p.Gly765Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,611,428 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.279

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00852859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.2294G>A	p.Gly765Glu	missense_variant	19/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.2321G>A	p.Gly774Glu	missense_variant	19/21
PIWIL3	NR_045648.1	n.2925G>A		non_coding_transcript_exon_variant	20/22
PIWIL3	NR_045649.2	n.2798G>A		non_coding_transcript_exon_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.2294G>A	p.Gly765Glu	missense_variant	19/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.2321G>A	p.Gly774Glu	missense_variant	19/21	1		P2
PIWIL3	ENST00000527701.6	c.*2266G>A		3_prime_UTR_variant, NMD_transcript_variant	20/22	1
PIWIL3	ENST00000533313.6	c.*2220G>A		3_prime_UTR_variant, NMD_transcript_variant	20/22	1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251238 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135814

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1459166 Hom.: 1 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 726074

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000784

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74454

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000710

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Feb 28, 2023

The c.2321G>A (p.G774E) alteration is located in exon 19 (coding exon 18) of the PIWIL3 gene. This alteration results from a G to A substitution at nucleotide position 2321, causing the glycine (G) at amino acid position 774 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.5
Dann	Benign	0.52
DEOGEN2	Benign	0.0047	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.44	T;.;.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0085	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.44	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.36	B;B;B;B
Vest4		0.22
MVP		0.21
MPC		0.15
ClinPred		0.013	T
GERP RS		-2.2
Varity_R		0.049
gMVP		0.073

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: rs139246673; hg19: chr22-25119160; COSMIC: COSV100177720;