22-24727968-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001255975.1(PIWIL3):c.1991C>T(p.Thr664Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79

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]

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=0.06850448).
• BP6: Variant 22-24727968-G-A is Benign according to our data. Variant chr22-24727968-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2477906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1991C>T	p.Thr664Ile	missense_variant	16/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.2018C>T	p.Thr673Ile	missense_variant	16/21
PIWIL3	NR_045648.1	n.2622C>T		non_coding_transcript_exon_variant	17/22
PIWIL3	NR_045649.2	n.2495C>T		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1991C>T	p.Thr664Ile	missense_variant	16/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.2018C>T	p.Thr673Ile	missense_variant	16/21	1		P2
PIWIL3	ENST00000527701.6	c.*1963C>T		3_prime_UTR_variant, NMD_transcript_variant	17/22	1
PIWIL3	ENST00000533313.6	c.*1917C>T		3_prime_UTR_variant, NMD_transcript_variant	17/22	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460568 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726652

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.17
Dann	Benign	0.82
DEOGEN2	Benign	0.0020	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.27	T;.;.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.83	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.015	B;B;B;B
Vest4		0.088
MutPred		0.66		Loss of catalytic residue at T673 (P = 0.0133);Loss of catalytic residue at T673 (P = 0.0133);.;.;
MVP		0.040
MPC		0.12
ClinPred		0.058	T
GERP RS		-1.2
Varity_R		0.020
gMVP		0.056

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: chr22-25123935;