12-130349232-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004764.5(PIWIL1):c.735-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,609,448 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (150 hom.)
• Consequence: PIWIL1 NM_004764.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002403
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.08

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-130349232-C-T is Benign according to our data. Variant chr12-130349232-C-T is described in ClinVar as [Benign]. Clinvar id is 3056328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0128 (18679/1457156) while in subpopulation NFE AF= 0.0153 (16933/1107902). AF 95% confidence interval is 0.0151. There are 150 homozygotes in gnomad4_exome. There are 9085 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL1	NM_004764.5	c.735-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000245255.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL1	ENST00000245255.7	c.735-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004764.5	P1
PIWIL1	ENST00000540672.2	n.992-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1479 AN: 152174 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00948 AC: 2382 AN: 251302 Hom.: 19 AF XY: 0.00953 AC XY: 1295 AN XY: 135828

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000916

Gnomad FIN exome AF: 0.00518

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0128 AC: 18679 AN: 1457156 Hom.: 150 Cov.: 31 AF XY: 0.0125 AC XY: 9085 AN XY: 724030

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000824

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.00971 AC: 1479 AN: 152292 Hom.: 9 Cov.: 33 AF XY: 0.00927 AC XY: 690 AN XY: 74472

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0123 Hom.: 8

Bravo AF: 0.0101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0166

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PIWIL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2019

This variant is classified as 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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.81
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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: rs117552783; hg19: chr12-130833777;