22-24723214-G-A

Variant names:

• chr22-24723214-G-A
• rs1459408352
• NM_001255975.1:c.2273C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001255975.1(PIWIL3):​c.2273C>T​(p.Thr758Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL3	NM_001255975.1	MANE Select	c.2273C>T	p.Thr758Ile	missense	Exon 19 of 21	NP_001242904.1	B4DYF7
	PIWIL3	NM_001008496.3		c.2300C>T	p.Thr767Ile	missense	Exon 19 of 21	NP_001008496.2	Q7Z3Z3
	PIWIL3	NR_045648.1		n.2904C>T		non_coding_transcript_exon	Exon 20 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL3	ENST00000616349.5	TSL:1 MANE Select	c.2273C>T	p.Thr758Ile	missense	Exon 19 of 21	ENSP00000479524.2	A0A8J9G8U8
	PIWIL3	ENST00000332271.9	TSL:1	c.2300C>T	p.Thr767Ile	missense	Exon 19 of 21	ENSP00000330031.5	Q7Z3Z3
	PIWIL3	ENST00000527701.6	TSL:1	n.*2245C>T		non_coding_transcript_exon	Exon 20 of 22	ENSP00000435718.2	E9PIP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458016 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725602

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108932

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0042	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Benign	0.043	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.51
MutPred		0.73		Gain of sheet (P = 0.0827)
MVP		0.48
MPC		0.53
ClinPred		0.97	D
GERP RS		1.5
Varity_R		0.10
gMVP		0.36
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1459408352; hg19: chr22-25119181; COSMIC: COSV59998658;