22-24748945-C-T

Variant names:

• chr22-24748945-C-T
• rs11703684
• NM_001255975.1:c.1411G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 30 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
PIWIL3	NM_001255975.1	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 21	ENST00000616349.5	NP_001242904.1
PIWIL3	NM_001008496.3	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 21		NP_001008496.2
PIWIL3	NR_045648.1	n.2042G>A		non_coding_transcript_exon_variant	Exon 13 of 22
PIWIL3	NR_045649.2	n.1915G>A		non_coding_transcript_exon_variant	Exon 13 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 21	1	NM_001255975.1	ENSP00000479524.2

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

GnomAD2 exomes AF: 0.232 AC: 58157 AN: 250202 AF XY: 0.225

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 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

African (AFR) AF: 0.146 AC: 4889 AN: 33396

American (AMR) AF: 0.420 AC: 18622 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4842 AN: 26094

East Asian (EAS) AF: 0.196 AC: 7774 AN: 39642

South Asian (SAS) AF: 0.180 AC: 15476 AN: 86040

European-Finnish (FIN) AF: 0.210 AC: 11209 AN: 53340

Middle Eastern (MID) AF: 0.162 AC: 935 AN: 5760

European-Non Finnish (NFE) AF: 0.216 AC: 239617 AN: 1110478

Other (OTH) AF: 0.201 AC: 12118 AN: 60302

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

African (AFR) AF: 0.152 AC: 6293 AN: 41494

American (AMR) AF: 0.318 AC: 4855 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 619 AN: 3468

East Asian (EAS) AF: 0.167 AC: 864 AN: 5174

South Asian (SAS) AF: 0.184 AC: 887 AN: 4814

European-Finnish (FIN) AF: 0.210 AC: 2225 AN: 10596

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14675 AN: 67968

Other (OTH) AF: 0.207 AC: 437 AN: 2112

Alfa AF: 0.208 Hom.: 11590

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;.;.
PhyloP100		-0.064
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.33	.;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.47	.;T;T;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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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