chr22-24728348-G-T

Position:

• chr22-24728348-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001255975.1(PIWIL3):​c.1734C>A​(p.Asp578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.07

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067298174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIWIL3	NM_001255975.1	c.1734C>A	p.Asp578Glu	missense_variant	15/21	ENST00000616349.5	NP_001242904.1
PIWIL3	NM_001008496.3	c.1761C>A	p.Asp587Glu	missense_variant	15/21		NP_001008496.2
PIWIL3	NR_045648.1	n.2365C>A		non_coding_transcript_exon_variant	16/22
PIWIL3	NR_045649.2	n.2238C>A		non_coding_transcript_exon_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1734C>A	p.Asp578Glu	missense_variant	15/21	1	NM_001255975.1	ENSP00000479524.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Jan 02, 2024

The c.1761C>A (p.D587E) alteration is located in exon 15 (coding exon 14) of the PIWIL3 gene. This alteration results from a C to A substitution at nucleotide position 1761, causing the aspartic acid (D) at amino acid position 587 to be replaced by a glutamic acid (E). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.73
DEOGEN2	Benign	0.0053	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.33	T;.;.;T
M_CAP	Benign	0.00053	T
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	.;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.051	.;T;D;D
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.012	B;B;B;B
Vest4		0.032
MutPred		0.56		Gain of methylation at K588 (P = 0.0765);Gain of methylation at K588 (P = 0.0765);.;.;
MVP		0.25
MPC		0.10
ClinPred		0.25	T
GERP RS		-4.1
Varity_R		0.052
gMVP		0.043

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

Other links and lift over

dbSNP: rs1274458997; hg19: chr22-25124315;