22-24719573-G-C

Position:

• chr22-24719573-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001255975.1(PIWIL3):​c.2521C>G​(p.Pro841Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53

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 (HGNC:):

ACMG classification

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, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIWIL3	NM_001255975.1	c.2521C>G	p.Pro841Ala	missense_variant	21/21	ENST00000616349.5	NP_001242904.1
PIWIL3	NM_001008496.3	c.2548C>G	p.Pro850Ala	missense_variant	21/21		NP_001008496.2
PIWIL3	NR_045648.1	n.3152C>G		non_coding_transcript_exon_variant	22/22
PIWIL3	NR_045649.2	n.3025C>G		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5	c.2521C>G	p.Pro841Ala	missense_variant	21/21	1	NM_001255975.1	ENSP00000479524.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.2548C>G (p.P850A) alteration is located in exon 21 (coding exon 20) of the PIWIL3 gene. This alteration results from a C to G substitution at nucleotide position 2548, causing the proline (P) at amino acid position 850 to be replaced by an alanine (A). 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	0.95
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;.;.;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.6	.;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.52
MutPred		0.88		Gain of catalytic residue at P850 (P = 0.0752);Gain of catalytic residue at P850 (P = 0.0752);.;.;
MVP		0.81
MPC		0.53
ClinPred		0.92	D
GERP RS		2.1
Varity_R		0.74
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-25115540;