Variant 22-24724919-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001255975.1(PIWIL3):c.2199G>A(p.Met733Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 ( 0 hom. )

Consequence

PIWIL3
NM_001255975.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.104

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.042833865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIWIL3	NM_001255975.1 linkuse as main transcript	c.2199G>A	p.Met733Ile	missense_variant	18/21	ENST00000616349.5
PIWIL3	NM_001008496.3 linkuse as main transcript	c.2226G>A	p.Met742Ile	missense_variant	18/21
PIWIL3	NR_045648.1 linkuse as main transcript	n.2830G>A		non_coding_transcript_exon_variant	19/22
PIWIL3	NR_045649.2 linkuse as main transcript	n.2703G>A		non_coding_transcript_exon_variant	19/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PIWIL3	ENST00000616349.5 linkuse as main transcript	c.2199G>A	p.Met733Ile	missense_variant	18/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9 linkuse as main transcript	c.2226G>A	p.Met742Ile	missense_variant	18/21	1		P2
PIWIL3	ENST00000527701.6 linkuse as main transcript	c.*2171G>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	1
PIWIL3	ENST00000533313.6 linkuse as main transcript	c.*2125G>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251302

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.2226G>A (p.M742I) alteration is located in exon 18 (coding exon 17) of the PIWIL3 gene. This alteration results from a G to A substitution at nucleotide position 2226, causing the methionine (M) at amino acid position 742 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

0.25

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

Cadd

Benign

0.053

Dann

Benign

0.48

DEOGEN2

Benign

0.0023

T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.47

T;.;.;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.85

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.51

Sift4G

Benign

0.84

T;T;T;T

Polyphen

0.0090

B;B;B;B

Vest4

0.18

MutPred

0.56

Loss of ubiquitination at K741 (P = 0.0369);Loss of ubiquitination at K741 (P = 0.0369);.;.;

MVP

0.12

MPC

0.12

ClinPred

0.021

GERP RS

-3.6

Varity_R

0.064

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over