22-24734110-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.1681A>G(p.Lys561Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,612,790 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 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.340

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=0.013651609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1681A>G	p.Lys561Glu	missense_variant	14/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.1681A>G	p.Lys561Glu	missense_variant	14/21
PIWIL3	NR_045648.1	n.2312A>G		non_coding_transcript_exon_variant	15/22
PIWIL3	NR_045649.2	n.2185A>G		non_coding_transcript_exon_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1681A>G	p.Lys561Glu	missense_variant	14/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.1681A>G	p.Lys561Glu	missense_variant	14/21	1		P2
PIWIL3	ENST00000527701.6	c.*1653A>G		3_prime_UTR_variant, NMD_transcript_variant	15/22	1
PIWIL3	ENST00000533313.6	c.*1607A>G		3_prime_UTR_variant, NMD_transcript_variant	15/22	1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000478

GnomAD3 exomes AF: 0.0000760 AC: 19 AN: 249966 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135042

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.0000880

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: 0.0000246 AC: 36 AN: 1460488 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726432

Gnomad4 AFR exome AF: 0.000957

Gnomad4 AMR exome AF: 0.0000898

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74484

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000196

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: 0.000473

Alfa AF: 0.0000616 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

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

Aug 08, 2022

The c.1681A>G (p.K561E) 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 1681, causing the lysine (K) at amino acid position 561 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	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	4.8
Dann	Benign	0.52
DEOGEN2	Benign	0.0019	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.44	T;.;.;T
M_CAP	Benign	0.00063	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.63	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.11	B;B;B;B
Vest4		0.15
MVP		0.19
MPC		0.16
ClinPred		0.0046	T
GERP RS		-0.30
Varity_R		0.064
gMVP		0.057

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: rs139139116; hg19: chr22-25130077;