22-24723244-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001255975.1(PIWIL3):c.2243C>A(p.Ala748Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,610,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PIWIL3
NM_001255975.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIWIL3	NM_001255975.1 linkuse as main transcript	c.2243C>A	p.Ala748Asp	missense_variant	19/21	ENST00000616349.5
PIWIL3	NM_001008496.3 linkuse as main transcript	c.2270C>A	p.Ala757Asp	missense_variant	19/21
PIWIL3	NR_045648.1 linkuse as main transcript	n.2874C>A		non_coding_transcript_exon_variant	20/22
PIWIL3	NR_045649.2 linkuse as main transcript	n.2747C>A		non_coding_transcript_exon_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PIWIL3	ENST00000616349.5 linkuse as main transcript	c.2243C>A	p.Ala748Asp	missense_variant	19/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9 linkuse as main transcript	c.2270C>A	p.Ala757Asp	missense_variant	19/21	1		P2
PIWIL3	ENST00000527701.6 linkuse as main transcript	c.*2215C>A		3_prime_UTR_variant, NMD_transcript_variant	20/22	1
PIWIL3	ENST00000533313.6 linkuse as main transcript	c.*2169C>A		3_prime_UTR_variant, NMD_transcript_variant	20/22	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250478

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458224

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725668

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:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000283

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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

Jun 12, 2023

The c.2270C>A (p.A757D) alteration is located in exon 19 (coding exon 18) of the PIWIL3 gene. This alteration results from a C to A substitution at nucleotide position 2270, causing the alanine (A) at amino acid position 757 to be replaced by an aspartic acid (D). 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

0.93

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.087

T;T;.;.

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

T;.;.;T

M_CAP

Benign

0.0022

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.;.

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Benign

0.46

Sift4G

Uncertain

0.042

D;D;D;D

Polyphen

1.0

D;D;P;P

Vest4

0.66

MutPred

0.81

Loss of MoRF binding (P = 0.0731);Loss of MoRF binding (P = 0.0731);.;.;

MVP

0.50

MPC

0.38

ClinPred

0.80

GERP RS

2.7

Varity_R

0.35

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 0

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