22-24748945-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001255975.1(PIWIL3):c.1411G>A(p.Val471Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,611,530 control chromosomes in the GnomAD database, including 39,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3509 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35963 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00345546).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1411G>A	p.Val471Ile	missense_variant	12/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.1411G>A	p.Val471Ile	missense_variant	12/21
PIWIL3	NR_045648.1	n.2042G>A		non_coding_transcript_exon_variant	13/22
PIWIL3	NR_045649.2	n.1915G>A		non_coding_transcript_exon_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1411G>A	p.Val471Ile	missense_variant	12/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.1411G>A	p.Val471Ile	missense_variant	12/21	1		P2
PIWIL3	ENST00000527701.6	c.*1383G>A		3_prime_UTR_variant, NMD_transcript_variant	13/22	1
PIWIL3	ENST00000533313.6	c.*1337G>A		3_prime_UTR_variant, NMD_transcript_variant	13/22	1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31118 AN: 151988 Hom.: 3510 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.232 AC: 58157 AN: 250202 Hom.: 7857 AF XY: 0.225 AC XY: 30445 AN XY: 135212

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.216 AC: 315482 AN: 1459424 Hom.: 35963 Cov.: 32 AF XY: 0.214 AC XY: 155645 AN XY: 726006

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.205 AC: 31130 AN: 152106 Hom.: 3509 Cov.: 32 AF XY: 0.206 AC XY: 15317 AN XY: 74358

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.207

Alfa AF: 0.208 Hom.: 8410

Bravo AF: 0.214

TwinsUK AF: 0.225 AC: 834

ALSPAC AF: 0.221 AC: 851

ESP6500AA AF: 0.147 AC: 648

ESP6500EA AF: 0.214 AC: 1837

ExAC AF: 0.224 AC: 27226

Asia WGS AF: 0.164 AC: 570 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.210

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.21
Dann	Benign	0.61
DEOGEN2	Benign	0.0050	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	T;.;.;T
MetaRNN	Benign	0.0035	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;L;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.10	B;B;B;B
Vest4		0.024
MPC		0.088
ClinPred		0.00042	T
GERP RS		-3.9
Varity_R		0.021
gMVP		0.049

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

LitVar

Other links and lift over

dbSNP: rs11703684; hg19: chr22-25144912; COSMIC: COSV59994716;