Variant 22-24719551-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001255975.1(PIWIL3):c.2543A>G(p.His848Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,605,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PIWIL3
NM_001255975.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20

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:

PIWIL3 (HGNC:):

PIWIL3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIWIL3	NM_001255975.1 linkuse as main transcript	c.2543A>G	p.His848Arg	missense_variant	21/21	ENST00000616349.5	NP_001242904.1	A0A8J9G8U8B4DYF7
PIWIL3	NM_001008496.3 linkuse as main transcript	c.2570A>G	p.His857Arg	missense_variant	21/21		NP_001008496.2	Q7Z3Z3
PIWIL3	NR_045648.1 linkuse as main transcript	n.3174A>G		non_coding_transcript_exon_variant	22/22
PIWIL3	NR_045649.2 linkuse as main transcript	n.3047A>G		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5 linkuse as main transcript	c.2543A>G	p.His848Arg	missense_variant	21/21	1	NM_001255975.1	ENSP00000479524.2		A0A8J9G8U8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722560

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.0000312

Hom.:

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

Sep 27, 2024

The c.2570A>G (p.H857R) alteration is located in exon 21 (coding exon 20) of the PIWIL3 gene. This alteration results from a A to G substitution at nucleotide position 2570, causing the histidine (H) at amino acid position 857 to be replaced by an arginine (R). 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

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

T;T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

-0.0076

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

T;.;.;T

M_CAP

Benign

0.0029

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.8

M;M;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.1

.;D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.039

.;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.73

MutPred

0.88

Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;.;

MVP

0.46

MPC

0.54

ClinPred

0.98

GERP RS

2.1

Varity_R

0.49

gMVP

0.57

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