22-24719813-C-T

Position:

• chr22-24719813-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001255975.1(PIWIL3):​c.2440G>A​(p.Gly814Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,611,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.200

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112157345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIWIL3	NM_001255975.1	c.2440G>A	p.Gly814Ser	missense_variant	20/21	ENST00000616349.5	NP_001242904.1
PIWIL3	NM_001008496.3	c.2467G>A	p.Gly823Ser	missense_variant	20/21		NP_001008496.2
PIWIL3	NR_045648.1	n.3071G>A		non_coding_transcript_exon_variant	21/22
PIWIL3	NR_045649.2	n.2944G>A		non_coding_transcript_exon_variant	21/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5	c.2440G>A	p.Gly814Ser	missense_variant	20/21	1	NM_001255975.1	ENSP00000479524.2

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251428 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000358 AC: 523 AN: 1459462 Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 726266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000446

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74312

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000669 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000709

EpiControl AF: 0.000415

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

Dec 02, 2022

The c.2467G>A (p.G823S) alteration is located in exon 20 (coding exon 19) of the PIWIL3 gene. This alteration results from a G to A substitution at nucleotide position 2467, causing the glycine (G) at amino acid position 823 to be replaced by a serine (S). 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	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.47
DANN	Benign	0.93
DEOGEN2	Benign	0.018	T;T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.74	T;.;.;T
M_CAP	Benign	0.00080	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	.;D;D;D
REVEL	Benign	0.088
Sift	Uncertain	0.021	.;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.94	P;P;P;P
Vest4		0.31
MVP		0.19
MPC		0.22
ClinPred		0.13	T
GERP RS		-5.6
Varity_R		0.12
gMVP		0.091

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: rs199855233; hg19: chr22-25115780;