22-24734125-T-C

Variant summary

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

The NM_001255975.1(PIWIL3):c.1666A>G(p.Ile556Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,742 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.485

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=0.041558713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1666A>G	p.Ile556Val	missense_variant	14/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.1666A>G	p.Ile556Val	missense_variant	14/21
PIWIL3	NR_045648.1	n.2297A>G		non_coding_transcript_exon_variant	15/22
PIWIL3	NR_045649.2	n.2170A>G		non_coding_transcript_exon_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1666A>G	p.Ile556Val	missense_variant	14/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.1666A>G	p.Ile556Val	missense_variant	14/21	1		P2
PIWIL3	ENST00000527701.6	c.*1638A>G		3_prime_UTR_variant, NMD_transcript_variant	15/22	1
PIWIL3	ENST00000533313.6	c.*1592A>G		3_prime_UTR_variant, NMD_transcript_variant	15/22	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250280 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Jun 02, 2023

The c.1666A>G (p.I556V) alteration is located in exon 14 (coding exon 13) of the PIWIL3 gene. This alteration results from a A to G substitution at nucleotide position 1666, causing the isoleucine (I) at amino acid position 556 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.30
Dann	Benign	0.24
DEOGEN2	Benign	0.0041	T;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.38	T;.;.;T
M_CAP	Benign	0.00039	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.63	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.11	B;B;B;B
Vest4		0.072
MutPred		0.29		Gain of ubiquitination at K561 (P = 0.1278);Gain of ubiquitination at K561 (P = 0.1278);.;.;
MVP		0.19
MPC		0.092
ClinPred		0.082	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.039

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: rs772325698; hg19: chr22-25130092;