dbSNP rs1383546384: PIWIL3:p.Gly836Val (chr22-24719587-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001255975.1(PIWIL3):c.2507G>T(p.Gly836Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000699 in 1,430,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G836D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PIWIL3
NM_001255975.1 missense, splice_region

Scores

Splicing: ADA: 0.1084

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.05

Publications

0 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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

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	UniProt
PIWIL3	NM_001255975.1	MANE Select	c.2507G>T	p.Gly836Val	missense splice_region	Exon 21 of 21	NP_001242904.1	B4DYF7
PIWIL3	NM_001008496.3		c.2534G>T	p.Gly845Val	missense splice_region	Exon 21 of 21	NP_001008496.2	Q7Z3Z3
PIWIL3	NR_045648.1		n.3138G>T		splice_region non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIWIL3	ENST00000616349.5	TSL:1 MANE Select	c.2507G>T	p.Gly836Val	missense splice_region	Exon 21 of 21	ENSP00000479524.2	A0A8J9G8U8
PIWIL3	ENST00000332271.9	TSL:1	c.2534G>T	p.Gly845Val	missense splice_region	Exon 21 of 21	ENSP00000330031.5	Q7Z3Z3
PIWIL3	ENST00000527701.6	TSL:1	n.*2479G>T		splice_region non_coding_transcript_exon	Exon 22 of 22	ENSP00000435718.2	E9PIP6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709866

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31760

American (AMR)

AF:

0.00

AC:

AN:

36944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

80766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100070

Other (OTH)

AF:

0.00

AC:

AN:

58978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0049

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.78

MutationAssessor

Pathogenic

3.4

PhyloP100

4.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.5

REVEL

Benign

0.26

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MutPred

0.89

Gain of sheet (P = 0.1539)

MVP

0.55

MPC

0.60

ClinPred

1.0

GERP RS

2.1

Varity_R

0.42

gMVP

0.63

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.18

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over