12-130343005-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004764.5(PIWIL1):c.94T>G(p.Tyr32Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,930 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y32C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0097 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (29 hom.)
• Consequence: PIWIL1 NM_004764.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

Genes affected

PIWIL1 (HGNC:9007): (piwi like RNA-mediated gene silencing 1) This gene encodes a member of the PIWI subfamily of Argonaute proteins, evolutionarily conserved proteins containing both PAZ and Piwi motifs that play important roles in stem cell self-renewal, RNA silencing, and translational regulation in diverse organisms. The encoded protein may play a role as an intrinsic regulator of the self-renewal capacity of germline and hematopoietic stem cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PIWIL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026398003).
• BP6: Variant 12-130343005-T-G is Benign according to our data. Variant chr12-130343005-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3056689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00973 (1482/152344) while in subpopulation AFR AF= 0.034 (1415/41576). AF 95% confidence interval is 0.0326. There are 25 homozygotes in gnomad4. There are 696 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL1	NM_004764.5	c.94T>G	p.Tyr32Asp	missense_variant	3/21	ENST00000245255.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL1	ENST00000245255.7	c.94T>G	p.Tyr32Asp	missense_variant	3/21	1	NM_004764.5	P1

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1474 AN: 152226 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00255 AC: 642 AN: 251442 Hom.: 5 AF XY: 0.00176 AC XY: 239 AN XY: 135902

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000991 AC: 1448 AN: 1461586 Hom.: 29 Cov.: 31 AF XY: 0.000884 AC XY: 643 AN XY: 727110

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00973 AC: 1482 AN: 152344 Hom.: 25 Cov.: 33 AF XY: 0.00934 AC XY: 696 AN XY: 74494

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00185 Hom.: 7

Bravo AF: 0.0113

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PIWIL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.027	T;T;T;.;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.33	N
MetaRNN	Benign	0.0026	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.29	N;N;N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.20	T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.62	P;.;.;.;.;.
Vest4		0.42
MVP		0.53
MPC		1.9
ClinPred		0.013	T
GERP RS		3.9
Varity_R		0.083
gMVP		0.43

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: rs75876550; hg19: chr12-130827550;