22-24724981-A-G

Variant summary

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

The NM_001255975.1(PIWIL3):ā€‹c.2137T>Cā€‹(p.Tyr713His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,850 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: not found (cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

PIWIL3
NM_001255975.1 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.26
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]

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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, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIWIL3NM_001255975.1 linkuse as main transcriptc.2137T>C p.Tyr713His missense_variant 18/21 ENST00000616349.5 NP_001242904.1 A0A8J9G8U8B4DYF7
PIWIL3NM_001008496.3 linkuse as main transcriptc.2164T>C p.Tyr722His missense_variant 18/21 NP_001008496.2 Q7Z3Z3
PIWIL3NR_045648.1 linkuse as main transcriptn.2768T>C non_coding_transcript_exon_variant 19/22
PIWIL3NR_045649.2 linkuse as main transcriptn.2641T>C non_coding_transcript_exon_variant 19/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIWIL3ENST00000616349.5 linkuse as main transcriptc.2137T>C p.Tyr713His missense_variant 18/211 NM_001255975.1 ENSP00000479524.2 A0A8J9G8U8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135910
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461850
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

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 submitterclinical testingAmbry GeneticsOct 19, 2024The c.2164T>C (p.Y722H) alteration is located in exon 18 (coding exon 17) of the PIWIL3 gene. This alteration results from a T to C substitution at nucleotide position 2164, causing the tyrosine (Y) at amino acid position 722 to be replaced by a histidine (H). 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
0.99
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;T;.;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;.;.;D
M_CAP
Benign
0.0081
T
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
-0.073
T
MutationAssessor
Pathogenic
3.6
H;H;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-4.3
.;D;D;D
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.75
MutPred
0.91
Gain of disorder (P = 0.0317);Gain of disorder (P = 0.0317);.;.;
MVP
0.55
MPC
0.61
ClinPred
1.0
D
GERP RS
3.4
Varity_R
0.78
gMVP
0.42

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.

Other links and lift over

dbSNP: rs1451666203; hg19: chr22-25120948; API