Genetic Variant NM_001255975.1:c.1411G>C (chr22-24748945-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001255975.1(PIWIL3):c.1411G>C(p.Val471Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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)

Consequence

PIWIL3
NM_001255975.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0640

Publications

30 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065521896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001255975.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIWIL3	NM_001255975.1	MANE Select	c.1411G>C	p.Val471Leu	missense	Exon 12 of 21	NP_001242904.1
PIWIL3	NM_001008496.3		c.1411G>C	p.Val471Leu	missense	Exon 12 of 21	NP_001008496.2
PIWIL3	NR_045648.1		n.2042G>C		non_coding_transcript_exon	Exon 13 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIWIL3	ENST00000616349.5	TSL:1 MANE Select	c.1411G>C	p.Val471Leu	missense	Exon 12 of 21	ENSP00000479524.2
PIWIL3	ENST00000332271.9	TSL:1	c.1411G>C	p.Val471Leu	missense	Exon 12 of 21	ENSP00000330031.5
PIWIL3	ENST00000527701.6	TSL:1	n.*1383G>C		non_coding_transcript_exon	Exon 13 of 22	ENSP00000435718.2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152050

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

11590

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.7

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0091

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.43

M_CAP

Benign

0.00064

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.064

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

REVEL

Benign

0.012

Sift

Benign

0.068

Sift4G

Benign

0.24

Polyphen

0.026

Vest4

0.090

MutPred

0.38

Loss of methylation at K473 (P = 0.0778)

MVP

0.072

MPC

0.11

ClinPred

0.12

GERP RS

-3.9

Varity_R

0.066

gMVP

0.10

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over