NM_004764.5:c.191-4dupT

Variant names:

• chr12-130345740-A-AT
• rs374456201
• NM_004764.5:c.191-4dupT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004764.5(PIWIL1):​c.191-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,547,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: PIWIL1 NM_004764.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.23
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-130345740-A-AT is Benign according to our data. Variant chr12-130345740-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 3056802.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004764.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL1	NM_004764.5	MANE Select	c.191-4dupT		splice_region intron	N/A	NP_004755.2	Q96J94-1
	PIWIL1	NM_001190971.2		c.191-4dupT		splice_region intron	N/A	NP_001177900.1	Q96J94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL1	ENST00000245255.7	TSL:1 MANE Select	c.191-4dupT		splice_region intron	N/A	ENSP00000245255.3	Q96J94-1
	PIWIL1	ENST00000542723.1	TSL:2	c.191-4dupT		splice_region intron	N/A	ENSP00000438582.1	F5H2F7
	PIWIL1	ENST00000546060.5	TSL:4	c.191-4dupT		splice_region intron	N/A	ENSP00000442086.1	F5H889

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151426 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000326 AC: 72 AN: 220652 AF XY: 0.000361

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.000359

Gnomad EAS exome AF: 0.0000613

Gnomad FIN exome AF: 0.000204

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000383

GnomAD4 exome AF: 0.000418 AC: 583 AN: 1396220 Hom.: 0 Cov.: 30 AF XY: 0.000438 AC XY: 304 AN XY: 694680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000534 AC: 17 AN: 31864

American (AMR) AF: 0.000373 AC: 16 AN: 42950

Ashkenazi Jewish (ASJ) AF: 0.000484 AC: 12 AN: 24788

East Asian (EAS) AF: 0.000425 AC: 16 AN: 37628

South Asian (SAS) AF: 0.000631 AC: 52 AN: 82440

European-Finnish (FIN) AF: 0.000214 AC: 11 AN: 51418

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5584

European-Non Finnish (NFE) AF: 0.000408 AC: 433 AN: 1061990

Other (OTH) AF: 0.000434 AC: 25 AN: 57558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151426 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73918

African (AFR) AF: 0.0000728 AC: 3 AN: 41202

American (AMR) AF: 0.0000659 AC: 1 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00403 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIWIL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs374456201; hg19: chr12-130830285; COSMIC: COSV55352665;