rs374456201

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-130345740-AT-A
• chr12-130345740-AT-ATT
• chr12-130345740-AT-ATTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004764.5(PIWIL1):​c.191-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,563,730 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (39 hom.)
• Consequence: PIWIL1 NM_004764.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00255 (387/151530) while in subpopulation SAS AF = 0.0191 (91/4766). AF 95% confidence interval is 0.0159. There are 6 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.191-4delT		splice_region intron	N/A	NP_004755.2	Q96J94-1
	PIWIL1	NM_001190971.2		c.191-4delT		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.191-4delT		splice_region intron	N/A	ENSP00000245255.3	Q96J94-1
	PIWIL1	ENST00000542723.1	TSL:2	c.191-4delT		splice_region intron	N/A	ENSP00000438582.1	F5H2F7
	PIWIL1	ENST00000546060.5	TSL:4	c.191-4delT		splice_region intron	N/A	ENSP00000442086.1	F5H889

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 384 AN: 151420 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00496 AC: 1095 AN: 220652 AF XY: 0.00559

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00323

Gnomad EAS exome AF: 0.00349

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00594

GnomAD4 exome AF: 0.00230 AC: 3247 AN: 1412200 Hom.: 39 Cov.: 30 AF XY: 0.00272 AC XY: 1910 AN XY: 702718

African (AFR) AF: 0.000589 AC: 19 AN: 32240

American (AMR) AF: 0.000254 AC: 11 AN: 43312

Ashkenazi Jewish (ASJ) AF: 0.00239 AC: 60 AN: 25064

East Asian (EAS) AF: 0.00250 AC: 95 AN: 38020

South Asian (SAS) AF: 0.0158 AC: 1313 AN: 83300

European-Finnish (FIN) AF: 0.0182 AC: 945 AN: 51840

Middle Eastern (MID) AF: 0.00302 AC: 17 AN: 5628

European-Non Finnish (NFE) AF: 0.000558 AC: 600 AN: 1074576

Other (OTH) AF: 0.00321 AC: 187 AN: 58220

GnomAD4 genome AF: 0.00255 AC: 387 AN: 151530 Hom.: 6 Cov.: 33 AF XY: 0.00359 AC XY: 266 AN XY: 74034

African (AFR) AF: 0.000557 AC: 23 AN: 41322

American (AMR) AF: 0.000263 AC: 4 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3460

East Asian (EAS) AF: 0.00639 AC: 33 AN: 5168

South Asian (SAS) AF: 0.0191 AC: 91 AN: 4766

European-Finnish (FIN) AF: 0.0152 AC: 159 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00102 AC: 69 AN: 67878

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Not reported in ClinVar

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)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 21

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: COSV55346241;